Peptide therapy with pentadecapeptide BPC 157 in

We focused on the healing of rat transected sciatic nerve and improvement made by stable gastric pentadecapeptide BPC 157 (10 microg, 10ng/kg) applied shortly after injury (i) intraperitoneally/intragastrically/locally, at the site of anastomosis, or after (ii) non-anastomozed nerve tubing (7 mm nerve segment resected) directly into the tube. Improvement was shown clinically (autotomy), microscopically/morphometrically and functionally (EMG, one or two months post-injury, walking recovery (sciatic functional index (SFI)) at weekly intervals). BPC 157-rats exhibited faster axonal regeneration: histomorphometrically (improved presentation of neural fascicles, homogeneous regeneration pattern, increased density and size of regenerative fibers, existence of epineural and perineural regeneration, uniform target orientation of regenerative fibers, and higher proportion of neural vs. connective tissue, all fascicles in each nerve showed increased diameter of myelinated fibers, thickness of myelin sheet, number of myelinated fibers per area and myelinated fibers as a percentage of the nerve transected area and the increased blood vessels presentation), electrophysiologically (increased motor action potentials), functionally (improved SFI), the autotomy absent. Thus, BPC 157 markedly improved rat sciatic nerve healing.

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... Notably, BPC 157 involves the counteraction of the other specific complications that would otherwise arise from the anastomosis malfunctioning and failing integrity of particular parts of the gastrointestinal tract depending on the site of anastomosis [40][41][42][43][44][45][46]. Furthermore, other anastomoses (i.e., sciatic nerve, abdominal aorta) were healed [47,48]. ...

... Given the suggested innate wound healing capability [2], the focus was on BPC 157 therapy in the healing of rat transected sciatic nerves [47]. In general, BPC 157 rats exhibited faster axonal regeneration histomorphometrically, electrophysiologically (increased motor action potentials), functionally (improved SFI), and with autotomy absent [47]. The presentation of neural fascicles, homogeneous regeneration pattern, density and size of regenerative fibers, existence of epineural and perineural regeneration, uniform target orientation of regenerative fibers, and higher proportion of neural vs. connective tissue were ...

Salem Bajramagic Marko Sever Fran Rašić

Predrag Sikiric

By introducing the healing of many distinctive anastomoses by BPC 157 therapy, this review practically deals with the concept of the resection and reconnection of the hollow parts of the gastrointestinal tract as one of the cornerstones of visceral surgery. In principle, the healing of quite distinctive anastomoses itself speaks for applied BPC 157 therapy, in particular, as a way in which the therapy of anastomoses can be successfully approached and carried out. Some of the anastomoses implicated were esophagogastric, colocolonic, jejunoileal, and ileoileal anastomoses, along with concomitant disturbances, such as esophagitis, sphincter dysfunction, failed intestinal adaptation, colitis, short bowel syndrome, major vessel occlusion, NO-system, and prostaglandins-system dysfunction, which were accordingly counteracted as well, and, finally, findings concerning other anastomoses healing (i.e., nerve and vessel). Moreover, the healing of fistulas, both external and internal, colocutaneous, gastrocutaneous, esophagocutaneous, duodenocutaneous, vesicovaginal, colovesical, and rectovaginal in rats, perceived as anastomoses made between two different tissues which are normally not connected, may also be indicative. This may be a particular reconnection of the parts of the gastrointestinal tract to re-establish adequate integrity depending on the tissue involved, given that both various intestinal anastomoses and various fistulas (intestinal and skin were accordingly healed simultaneously as the fistulas disappeared) were all healed.

... The prime injuries were induced centrally (i.e., spinal cord compression [76,77], stroke [38], brain trauma [78]). The other injuries were initiated at periphery (i.e., nerve transection [79], abdominal aorta occlusion [82], tumor cachexia [11], or application of neurotoxin [69,80], distinctive muscle relaxants [81], neuroleptics [68,70], L-arginine [86], L-NAME [70,86], alcohol acute and chronic intoxication [63,64], and electrolytes disturbances [54,[83][84][85]). Thus, this can be a common principle; BPC 157 therapy recovered all of these systemic muscle disabilities, peripheral and central, and the effects combined with cytoprotective capabilities (prime lesion attenuation) or neurotransmitter nerve-muscle effect clearly presented. ...

... Healing of transected rat sciatic nerve. First, we used the consistent failure of spontaneous healing of transected rat sciatic nerve in anastomosed nerve [79]. Consistently, we also used non-anastomosed nerves (7 mm nerve segment resected). ...

... These results with the evidence that BPC 157 markedly improved rat sciatic nerve healing. This was evidenced clinically (autotomy absent [79]; autotomy reflects chronic neuropathic pain, neuroma at the proximal nerve stump, regenerative nerve sprouts growing into all directions; counteracted pathophysiological impulses and increased spontaneous activity in the spinal dorsal horn at the segments of projection of the injured nerve [266]). Likewise, this was consistently evidenced histomorphometrically, electrophysiologically (increased motor action potentials), and functionally (walking recovery (sciatic functional index (SFI)) [79]. ...

Sanja Strbe

Predrag Sikiric

Alenka Boban Blagaic

Sven Seiwerth

We highlight the particular aspects of the stable gastric pentadecapeptide BPC 157 pleiotropic beneficial activity (not destroyed in human gastric juice, native and stable in human gastric juice, as a cytoprotection mediator holds a response specifically related to preventing or recovering damage as such) and its possible relations with neurotransmitter activity. We attempt to resolve the shortage of the pleiotropic beneficial effects of BPC 157, given the general standard neurotransmitter criteria, in classic terms. We substitute the lack of direct conclusive evidence (i.e., production within the neuron or present in it as a precursor molecule, released eliciting a response on the receptor on the target cells on neurons and being removed from the site of action once its signaling role is complete). This can be a network of interconnected evidence, previously envisaged in the implementation of the cytoprotection effects, consistent beneficial particular evidence that BPC 157 therapy counteracts dopamine, serotonin, glutamate, GABA, adrenalin/noradrenalin, acetylcholine, and NO-system disturbances. This specifically includes counteraction of those disturbances related to their receptors, both blockade and over-activity, destruction, depletion, tolerance, sensitization, and channel disturbances counteraction. Likewise, BPC 157 activates particular receptors (i.e., VGEF and growth hormone). Furthermore, close BPC 157/NO-system relations with the gasotransmitters crossing the cell membrane and acting directly on molecules inside the cell may envisage particular interactions with receptors on the plasma membrane of their target cells. Finally, there is nerve-muscle relation in various muscle disturbance counteractions, and nerve-nerve relation in various encephalopathies counteraction, which is also exemplified specifically by the BPC 157 therapy application.

... Considering the motoneuron regeneration, BPC 157 rats exhibited faster axonal regeneration as both local and general effect [146]. In particular, they presented improved presentation of neural fascicles, homogeneous regeneration pattern, increased density and size of regenerative fibers, existence of epineural and perineural regeneration, uniform target orientation of regenerative fibers, and a higher proportion of neural vs. connective tissue. ...

... All fascicles in each nerve showed increased diameter of myelinated fibers, thickness of myelin sheet, number of myelinated fibers per area and myelinated fibers as a percentage of the nerve transected area and the increased blood vessels presentation. The absent autotomy accords with the advanced healing, both electrophysiologically (increased motor action potentials) and functionally (improved walking as improved sciatic functional index (SFI)) [146]. In these terms, the evidence regarding both local and general effect confirms that the healing effect might be initiated at any time. ...

... The application was shortly after anastomosis injury, intraperitoneal or intragastric or local, at the site of anastomosis. Likewise, the application was later inserted into the tube with the non-anastomosed nerve after a 7-mm segment had been resected [146]. Considering the motoneuron regeneration, BPC 157 rats exhibited faster axonal regeneration as both local and general effect [146]. ...

Mario Staresinic Mladen Japjec

Hrvoje Vranes

Predrag Sikiric

First, we review the definitively severed myotendinous junction and recovery by the cytoprotective stable gastric pentadecapeptide BPC 157 therapy, its healing that might combine both transected and detached tendon and transected muscle, ligament and bone injuries, applied alone, as native peptide therapy, effective in rat injury, given intraperitoneally or in drinking water or topically, at the site of injury. As a follow up, we reviewed that with the BPC 157 therapy, its cytoprotective ability to organize simultaneous healing of different tissues of and full recovery of the myotendinous junction might represent the particular muscle therapy against distinctive etiopathology muscle disabilities and weakness. In this, BPC 157 therapy might recover many of muscle disabilities (i.e., succinylcholine, vascular occlusion, spinal cord compression, stroke, traumatic brain injury, severe electrolyte disturbances, neurotoxins, neuroleptics, alcohol, serotonin syndrome and NO-system blockade and tumor-cachexia). These might provide practical realization of the multimodal muscle-axis impact able to react depending on the condition and the given agent(s) and the symptoms distinctively related to the prime injurious cause symptoms in the wide healing concept, the concept of cytoprotection, in particular. Further, the BPC 157 therapy might be the recovery for the disabled heart functioning, and disabled smooth muscle functioning (various sphincters function recovery). Finally, BPC 157, native and stable in human gastric juice, might be a prototype of anti-ulcer cytoprotective peptide for the muscle therapy with high curing potential (very safe profile (lethal dose not achieved), with suited wide effective range (μg-ng regimens) and ways of application).

... There was also a strong wound-healing effect (for review, see, i.e., [3,102]). Thereby, there was the curing of the skin [53,55,[103][104][105], nerve [106], tendon [50,51,[107][108][109][110][111], muscle [110][111][112][113][114][115], ligament [116], and bone [117][118][119] injuries that spontaneously might not heal. In particular, there was a capability to simultaneously organize the healing of the different tissues (as an example occurred the healing of the osteotendinous junction [108,109] and the healing of the myotendinous junction [111] (and neuromuscular junction function recovering [68]) or the healing of the fistulas, external and internal [120]). ...

... In particular, there was a capability to simultaneously organize the healing of the different tissues (as an example occurred the healing of the osteotendinous junction [108,109] and the healing of the myotendinous junction [111] (and neuromuscular junction function recovering [68]) or the healing of the fistulas, external and internal [120]). Likewise, in particular regard for wounding [3,102], these realized healing effects in the various wounds [53,55,[103][104][105][106][107][108][109][110][111][112][113][114][115][116][117][118][119][120] might evidence the realized healing process after blood vessel are ruptured as a whole, and thereby, as we claimed [59], a distinctive effect on all four major events in clot formation and dissolution was fully accomplished. This meant a highly utilizable special effect, especially with heart failure therapy [18,19,23,24,[27][28][29]31,[37][38][39][40]. ...

... There is particular evidence noted with BPC 157 effects, in particular, wounding (i.e., abdominal aorta anastomosis [18] vs. amputation of the leg or tail [58][59][60], i.e., obstructing thrombus formation counteracted, and fully established the obstructing thrombus as rapidly annihilated [18] vs. decreased post-amputation bleeding [58][59][60]). Thus, we claimed that the realized healing effects in the various wound healing [53,55,[103][104][105][106][107][108][109][110][111][112][113][114][115][116][117][118][119][120] might be evidence of the realized healing process after a ruptured blood vessel as a whole. Thereby, it might be the innate distinctive effect on all four major events in clot formation and dissolution fully accomplished that might be distinctively used depending on the given injury and agent application. ...

Mario Udovicic

Predrag Sikiric Ivan Barisic

Sven Seiwerth

In heart disturbances, stable gastric pentadecapeptide BPC 157 especial therapy effects combine the therapy of myocardial infarction, heart failure, pulmonary hypertension arrhythmias, and thrombosis prevention and reversal. The shared therapy effect occurred as part of its even larger cytoprotection (cardioprotection) therapy effect (direct epithelial cell protection; direct endothelium cell protection) that BPC 157 exerts as a novel cytoprotection mediator, which is native and stable in human gastric juice, as well as easily applicable. Accordingly, there is interaction with many molecular pathways, combining maintained endothelium function and maintained thrombocytes function, which counteracted thrombocytopenia in rats that underwent major vessel occlusion and deep vein thrombosis and counteracted thrombosis in all vascular studies; the coagulation pathways were not affected. These appeared as having modulatory effects on NO-system (NO-release, NOS-inhibition, NO-over-stimulation all affected), controlling vasomotor tone and the activation of the Src-Caveolin-1-eNOS pathway and modulatory effects on the prostaglandins system (BPC 157 counteracted NSAIDs toxicity, counteracted bleeding, thrombocytopenia, and in particular, leaky gut syndrome). As an essential novelty noted in the vascular studies, there was the activation of the collateral pathways. This might be the upgrading of the minor vessel to take over the function of the disabled major vessel, competing with and counteracting the Virchow triad circumstances devastatingly present, making possible the recruitment of collateral blood vessels, compensating vessel occlusion and reestablishing the blood flow or bypassing the occluded or ruptured vessel. As a part of the counteraction of the severe vessel and multiorgan failure syndrome, counteracted were the brain, lung, liver, kidney, gastrointestinal lesions, and in particular, the counteraction of the heart arrhythmias and infarction.

... 1 Similarly, it was demonstrated that BPC-157 could also influence the healing of the transected nerve. 18 BPC-157 markedly improved rat sciatic nerve healing. The anti-ulcer peptidergic agent has a possible therapeutic effect in many neurological disturbances. ...

... 1 The wound-healing effect of BPC-157 is related to nerve healing. 18 BPC-157 has been studied for over two decades, and the mechanism of action is not clearly known. As far as is known, the beneficial effect on the periphery suggests a corresponding beneficial effect on central systems. 1 The observed beneficial effects were obtained within the specifically overstimulated or damaged dopaminergic, serotoninergic, GABAergic and opioid systems. 1 The ample evidence of the potential beneficial effects of BPC-157 includes its positive effect on many central disturbances, such as morphine-induced analgesia, morphine, and naloxone. ...

... These findings are very interesting, considering the essential role of NO in healing, and suggest the possibility of overriding of this negative effect and the neuroprotective capabilities of BPC-157. 18 BPC-157 is claimed to have beneficial effects even outside the gastrointestinal tract. Like many other gut peptides, BPC-157 is present in different organs and its possible special role in the interaction with the endothelium derived NO system. ...

Sang Yoong Park So Ron Choi Jeong Ho Kim Tae Young Lee

Objectives Body protective compound-157 (BPC-157) is a stable gastric pentadecapeptide that has been effective in trials aiming to increase wound healing capabilities and decrease inflammatory cell influx, including studies on the healing of muscles and tendons. There are no studies about the effect of BPC-157 on pain transmission via nociception. This study examined the antinociceptive effects of BPC-157 using formalin tests and immunohistochemistry. Methods Rats were randomly divided into the control, morphine and BPC-157 groups. Pain behavior was quantified periodically at 5- and 35- min intervals (representative values of phases 1 and 2) by counting the number of flinches exhibited by the injected paw after injection. The dorsal root ganglia (DRG) and spinal cords (SC) were collected, and then, the number of cytokine-positive cells was determined via immunostaining. Results BPC-157 dose-dependently decreased the number of flinches during phase 1 but did not decrease the number of flinches during phase 2. During phase 1, interleukin-1β (IL-1β) in the DRG tissue was significantly different in the morphine, 10 μg/kg BPC-157, and 20 μg/kg BPC-157 groups. During phase 2, statistical significance was achieved in the DRG tissue in the morphine, 20 μg/kg BPC-157, and 40 μg/kg BPC-157 groups. During phase 1, interleukin-6 was significantly different in the DRG tissue in the morphine group and the SC tissue in the 10 μg/kg BPC-157 group. During phase 2, statistical significance was achieved in the morphine group and the BPC-157 20 μg/kg group in both the DRG and SC tissues. There were no significant differences in tumor necrosis factor-α between the DRG and SC tissues. Conclusions BPC-157 was effective during phase 1 but not during phase 2, as determined by the formalin test. BPC-157 decreased the expression of IL-1β in the DRG tissue in phases 1 and 2.

... Finally, suggesting a particular generalization [4][5][6][7][8][9][10][11][12][13][14][15][16][17], this therapy's effect on fistulas/anastomosis [18][19][20][21][22][23][40][41][42][43][78][79][80][81], is also observed with the vessels anastomosis [82] as well as the nerve anastomosis [83]. Illustratively, after abdominal aorta anastomosis, BPC 157 actually prevents thrombosis development given shortly after anastomosis formation [82]. ...

... Noteworthy, this therapy results rapidly in the reversal of the hind legs failure [82]. In the healing of the rat transected sciatic nerve, the improvement was made by the stable gastric pentadecapeptide BPC 157 (10 microg, 10ng/kg) applied shortly after injury intraperitoneally/intragastrically/locally, at the site of anastomosis much like after non-anastomozed nerve tubing (7 mm nerve segment resected) when BPC 157 was applied directly into the tube [83]. The improvement was shown clinically (absent autotomy), microscopically/morphometrically and functionally (EMG, one or two months post-injury, walking recovery (sciatic functional index (SFI)) at weekly intervals [83]. ...

... In the healing of the rat transected sciatic nerve, the improvement was made by the stable gastric pentadecapeptide BPC 157 (10 microg, 10ng/kg) applied shortly after injury intraperitoneally/intragastrically/locally, at the site of anastomosis much like after non-anastomozed nerve tubing (7 mm nerve segment resected) when BPC 157 was applied directly into the tube [83]. The improvement was shown clinically (absent autotomy), microscopically/morphometrically and functionally (EMG, one or two months post-injury, walking recovery (sciatic functional index (SFI)) at weekly intervals [83]. ...

Marko Sever

Predrag Sikiric Domagoj Drmic

Sven Seiwerth

This review is focused on the healing of fistulas and stable gastric pentadecapeptide BPC 157. Assuming that the healing of the various wounds is essential also for the gastrointestinal fistulas healing, the healing effect on fistulas in rats, consistently noted with the stable gastric pentadecapeptide BPC 157, may raise several interesting possibilities. BPC 157 is originally an anti-ulcer agent, native to and stable in human gastric juice (for more than 24 h). Likely, it is a novel mediator of Robert’s cytoprotection maintaining gastrointestinal mucosal integrity. Namely, it is effective in the whole gastrointestinal tract, and heals various wounds (i.e., skin, muscle, tendon, ligament, bone; ulcers in the entire gastrointestinal tract; corneal ulcer); LD1 is not achieved. It is used in ulcerative colitis clinical trials, and now in multiple sclerosis, and addressed in several reviews. Therefore, it is not surprising that BPC 157 has documented consistent healing of the various gastrointestinal fistulas, external (esophagocutaneous, gastrocutaneous, duodenocutaneous, colocutaneous) and internal (colovesical, rectovaginal). Taking fistulas as a pathological connection, this rescue is verified with the beneficial effects in rats with the various gastrointestinal anastomoses, esophagogastric, jejunoileal, colo-colonic, ileoileal, esophagojejunal, esophagoduodenal, and gastrojejunal. This beneficial effect occurs equally when the gastrointestinal anastomoses are impaired with the application of NSAIDs, cysteamine, large bowel resection, as well as concomitant esophageal, gastric, and duodenal lesions and/or ulcerative colitis presentation, short bowel syndrome progression, liver and brain disturbances presentation. Particular aspects of the BPC 157 healing of the fistulas are especially emphasized.

... In other studies, it was shown that BPC 157 counteracts increased levels of proinflammatory and procachectic cytokines such as IL-6 and TNF-α [2]. Finally, BPC 157 improves sciatic nerve healing [41] when applied intraperitoneally, intragastrically, or locally at the site of anastomosis shortly after injury or directly into the tube after non-anastomosed nerve tubing (7mm nerve segment resection). ...

... Thereafter, the compound motor action potential (CMAP) was recorded from the same pair of electrodes after stimulating the first and second electrodes (a repetition of 1 Hz and a stimulus duration of 0.05 ms). The amplitude, polyphasic changes, and the proximal and distal CMAP latencies were recorded, and the nerve conduction velocity was calculated according to previous studies [41,43]. ...

... The specimens were dehydrated in graded ethanol solutions, embedded in paraffin, cut into 5-μm sections, deparaffinated in xylene, rehydrated in graded ethanol solutions, and mounted on glass slides. Representative field images of four caudal nerves from each tail were taken using light microscopy (magnification × 500) with a CCD camera using ISSA 3.1 software (VamStec, Zagreb) according to a previous study [41]. Axonal myelination was analyzed according to the following quantifications: (a) the total number of myelinated axons per 10,000 μm 2 ; (b) the number of myelinated axons with a diameter ≥ 7 μm per 10,000 μm 2 ; and (c) the average axonal diameter. ...

Darko Perovic Vide Bilic

Danijela Kolenc

Predrag Sikiric

Background: We focused on the therapeutic effects of the stable gastric pentadecapeptide BPC 157 in spinal cord injury using a rat model. BPC 157, of which the LD1 has not been achieved, has been implemented as an anti-ulcer peptide in inflammatory bowel disease trials and recently in a multiple sclerosis trial. In animals, BPC 157 has an anti-inflammatory effect and therapeutic effects in functional recovery and the rescue of somatosensory neurons in the sciatic nerve after transection, upon brain injury after concussive trauma, and in severe encephalopathies. Additionally, BPC 157 affects various molecular pathways. Methods: Therefore, BPC 157 therapy was administered by a one-time intraperitoneal injection (BPC 157 (200 or 2 μg/kg) or 0.9% NaCl (5 ml/kg)) 10 min after injury. The injury procedure involved laminectomy (level L2-L3) and a 60-s compression (neurosurgical piston (60-66 g) of the exposed dural sac of the sacrocaudal spinal cord). Assessments were performed at 1, 4, 7, 15, 30, 90, 180, and 360 days after injury. Results: All of the injured rats that received BPC 157 exhibited consistent clinical improvement, increasingly better motor function of the tail, no autotomy, and resolved spasticity by day 15. BPC 157 application largely counteracted changes at the microscopic level, including the formation of vacuoles and the loss of axons in the white matter, the formation of edema and the loss of motoneurons in the gray matter, and a decreased number of large myelinated axons in the rat caudal nerve from day 7. EMG recordings showed a markedly lower motor unit potential in the tail muscle. Conclusion: Axonal and neuronal necrosis, demyelination, and cyst formation were counteracted. The functional rescue provided by BPC 157 after spinal cord injury implies that BPC 157 therapy can impact all stages of the secondary injury phase.

... However, more important is the practical evidence from a considerable number of the studies, particularly in gastrointestinal research, that intragastric administration or per os administration in drinking water, is equally effective as injections of the supplement administered to rodents, which has been performed in the majority of studies on BPC 157. 12,41,43,48,51,54,55,58,59,[61][62][63][82][83][84][85]89,[91][92][93]98,114,116,117,[143][144][145][146][147][149][150][151][152][153][154][155] In reality, in particular along with its safety profile, LD-1 is not achieved, and there are no reported adverse effects in clinical trials; 1-13 this evidence suggests the ease of practical clinical application. point of homeostasis (cytoprotection/adaptive cytoprotection, organoprotection) in the body's maintenance of integrity. ...

... Thus, the healing of the esophagocutaneous, 82 gastrocutaneous, 83 duodenocutaneous, 84 colocutaneous, 85 vesicovaginalis, 86 and rectovaginalis fistulas, 87 assessed grossly, biomechanically and microscopically means demonstration of the both external and internal fistulas healing [82][83][84][85][86][87] and consequently, the realization of the simultaneous healing of different tissues. Likewise, is the demonstration of the improved anastomoses healing, 57,88-92 gastrointestinal (i.e., esophagogastric, esophagojejunal ileoileal, jejunoileal, colon anastomoses), 57,88-92 but also nerve (sciatic nerve) 93 and vascular (abdominal aorta). 94 Consequently, the evidence that it may close and heal the various fistulas 82-87 and improve anastomosis healing, 57,88-94 may be a proof of the fulfilled wound healing concept. ...

... 53 Sciatic nerve regeneration appears after transection with BPC 157 application, local (into the tube), intragastric or intraperitoneal. 93 After traumatic brain injury, it counteracts the otherwise progressing course. 104 In rat spinal cord compression with tail paralysis, axonal and neuronal necrosis, demyelination, cyst formation, BPC 157 result in marked recovery and rescues tail function in both short-terms and long-terms. ...

Ki-Baik Hahm

Alenka Boban Blagaic

Predrag Sikiric

Sven Seiwerth

We reviewed again the significance of the stable gastric pentadecapeptide BPC 157 as a likely mediator of Robert's stomach cytoprotection/adaptive cytoprotection and organoprotection and as novel mediator of Selye's stress coping response to reestablish homeostasis. Specific points of BPC 157 therapy and the original concept of Robert's cytoprotection/adaptive cytoprotection/organoprotection are discussed, including the beneficial effects of BPC 157. First, BPC 157 protects stomach cells and maintains gastric integrity against various noxious agents (Robert's killing cell by contact) and is continuously present in the gastric mucosa and gastric juice. Additionally, BPC 157 protects against the adverse effects of alcohol and nonsteroidal anti-inflammatory drugs on the gastric epithelium and other epithelia, that is, skin, liver, pancreas, heart (organoprotection), and brain, thereby suggesting its use in wound healing. Additionally, BPC 157 counteracts gastric endothelial injury that precedes and induces damage to the gastric epithelium and generalizes "gastric endothelial protection" to protection of the endothelium of other vessels (thrombosis, prolonged bleeding, and thrombocytopenia). BPC 157 also has an effect on blood vessels, resulting in vessel recruitment that circumvents vessel occlusion and the development of additional shunting and rapid bypass loops to rapidly reestablish the integrity of blood flow (ischemic/reperfusion colitis, duodenal lesions, cecal perforation, and inferior vena caval occlusion). Lastly, BPC 157 counteracts tumor cachexia, muscle wasting, and increases in pro-inflammatory/procachectic cytokines, such as interleukin-6 and tumor necrosis factor-α, and significantly corrects deranged muscle proliferation and myogenesis through changes in the expression of FoxO3a, p-AKT, p-mTOR, and P-GSK-3β (mitigating cancer cachexia).

... Of note, BPC 157 with "wound healing effect" [1][2][3][4][5][6] (i.e., that should be particularly considered as different tissues involved, skin [9][10][11], tendon [16][17][18][19], ligament [20], muscle [21][22][23][24], bone [25][26][27], nerve [46,47], cornea [48], gastrointestinal tract [12][13][14][15] and blood vessels [2,28,29], simultaneous healing of different tissues (i.e., fistulas [12,15,30])) markedly crosses the standard angiogenic growth peptides, i.e., a peptide given always alone, a peptide carrier free [1][2][3][4][5][6] vs. numerous carriers with standard angiogenic growth peptides (for review, see, i.e., [49,50]), a distinction that should be particularly considered. Interestingly, based on its healing capabilities, particular wound healing ability, Wood suggested that this anti-ulcer pentadecapeptide may be a solution for Pavlov's physiology concept [51]. ...

... In support, pentadecapeptide BPC 157 interacted with the somatosensory neurons and their function in ulcer healing (as well as in nasal mucosa healing and pain sensation) [149][150][151], and this led to nerve healing and regeneration [46,47], which is very important for muscle healing (providing nerve healing (regeneration of damaged intramuscular nerve branches) as prerequisite for muscle healing [152], and thereby, BPC 157 may successfully combine muscle healing and neuroprotective capabilities (i.e., we briefly reported the lack of atrophy even in long term after gracilis muscle had been denervated [24]). More specifically, BPC 157 markedly improved sciatic nerve regeneration after transection given intraperitoneally/intragastrically/locally, at the site of anastomosis, or after non-anastomozed nerve tubing (7 mm nerve segment resected), applied directly into the tube [46]. ...

Sven Seiwerth Rudolf Rucman Branko Turkovic

Predrag Sikiric

Commonly, the angiogenic growth factors signify healing. However, gastrointestinal ulceration is still poorly understood particularly with respect to a general pharmacological/pathophysiological role of various angiogenic growth factors implemented in growth factors wound healing concept. Thereby, we focused on the stable gastric pentadecapeptide BPC 157, a peptide given always alone vs. standard peptidergic angiogenic growth factors (EGF, FGF, VEGF), and numerous carriers. Further, we reviewed how the gastrointestinal tract healing could be generally perceived (i) in terms of angiogenic growth factors, and/or (ii) through the healing of extra-gastrointestinal tissues healing, such as tendon, ligament, muscle and bone, and vice versa. Respected were the beneficial effects obtained with free peptides or peptides with different carriers, EGF, FGF, VEGF, and BPC 157, their presentation along with injuries, and a healing commonality, providing their implementation in both gastrointestinal ulcer healing and tendon, ligament, muscle and bone healing. Only BPC 157 was consistently effective in all of the models of acute/chronic injury of esophagus, stomach, duodenum and lower gastrointestinal tract, intraperitoneally, per-orally or locally. Unlike bFGF-, EGF-, VEGF-gastrointestinal tract studies demonstrating improved healing, most of the studies on tendon, muscle and bone injuries provide evidence of their (increased) presentation along with the various procedures used to produce beneficial effects, compared to fewer studies in vitro, while in vivo healing has a limited number of studies, commonly limited to local application, diverse healing evidence with diverse carriers and delivery systems. Contrary to this, BPC 157 - using same regimens like in gastrointestinal healing studies - improves tendon, ligament and bone healing, accurately implementing its own angiogenic effect in the healing. Thus, we claim that just BPC 157 represents in practice a pharmacological and pathophysiological role of various peptidergic growth factors.

... The wound healing effect of BPC 157 related to the endothelium protection was noted in deep skin burns [29][30][31], transected/injured muscle [32][33][34], tendon, ligament [35][36][37][38][39][40] and bone (pseudoarthrosis, periodontitis) [23,41,42] and nerve [43] healing, as well as in particular tissues such as cornea [44]. BPC 157 interacts with nitric oxide (NO) system, both NOS-substrate (L-arginine) and NOS-blocker (L-NAME) in different models and species [15], including the regulation of a blood pressure [14]. ...

... Besides, with a direct neuroprotective effect, BPC 157 protects somatosensory neurons [67], strongly improves nerve regeneration after peripheral nerve transection and counteracts autotomy [43]. BPC 157 attenuated the course of traumatic brain injury, postponed deleterious outcome and counteracted the primary injury with respect to the secondary injury process [68]. ...

... Conceptually, in therapy terms of brain-gut axis we discuss together muscle healing [32][33][34] and neuroprotective capabilities [43,67,68] of BPC 157 with the counteracting effect on catalepsy (muscular rigidity and fixed posture regardless of external stimuli) and akinesia (inability to initiate movement) and thereby, on severely diminished dopaminergic cell activity which is involved in the direct pathway of movement [54,65]. Besides, the gastric lesions that appeared along with the catalepsy/akinesia development were accordingly counteracted and these phenomena may be particularly interesting [54,64,65]. ...

Predrag Sikiric

Sven Seiwerth Rucman Rudolf

Josipa Vlainić

Background: Brain-gut interaction involves, among others, peptidergic growth factors which are native in GI tract and have strong antiulcer potency and thus could from periphery beneficially affect CNS-disorders. We focused on the stable gastric pentadecapeptide BPC 157, an antiulcer peptidergic agent, safe in inflammatory bowel disease trials and now in multiple sclerosis trial, native and stable in human gastric juice. Methods: Review of our research on BPC 157 in terms of brain-gut axis. Results: BPC 157 may serve as a novel mediator of Robert's cytoprotection, involved in maintaining of GI mucosa integrity, with no toxic effect. BPC 157 was successful in the therapy of GI tract, periodontitis, liver and pancreas lesions, and in the healing of various tissues and wounds. Stimulated Egr-1 gene, NAB2, FAK-paxillin and JAK-2 pathways are hitherto implicated. Initially corresponding beneficial central influence was seen when BPC 157 was given peripherally and a serotonin release in particular brain areas, mostly nigrostriatal, was changed. BPC 157 modulates serotonergic and dopaminergic systems, beneficially affects various behavioral disturbances that otherwise appeared due to specifically (over)stimulated/damaged neurotransmitters systems. Besides, BPC 157 has neuroprotective effects: protects somatosensory neurons; peripheral nerve regeneration appearent after transection; after traumatic brain injury counteracts the otherwise progressing course, in rat spinal cord compression with tail paralysis, axonal and neuronal necrosis, demyelination, cyst formation and rescues tail function in both short-terms and long-terms; after NSAIDs or insulin overdose or cuprizone encephalopathies were attenuated along with GI, liver and vascular injuries. Conclusion: BPC 157,a gastric peptide, may serve as remedy in various nervous system disorders.

Predrag Sikiric

Sven Seiwerth Rucman Rudolf

Josipa Vlainić

... Total debridement of corneal epithelium was rescued with BPC 157 eye drops (mgor ng-regimen), and recovery was markedly accelerated in eyes on topical BPC 157 (Lazic et al., 2005); further, corneal transparency was maintained, and there was no formation of corneal neovascularization. In a series of acute and chronic injury models, BPC 157 consistently promoted healing after severe injuries in various tissues that were unable to heal spontaneously (Cerovecki et al., 2010;Cesarec et al., 2013;Chang et al., 2011;Gjurasin et al., 2010;Hrelec et al., 2009;Keremi et al., 2009;Klicek et al., 2008;Krivic et al., 2006Krivic et al., , 2008Mikus et al., 2001;Novinscak et al., 2008;Pevec et al., 2010;Sebecic et al., 1999;Seiwerth et al., 1997;Sever et al., 2009;Sikiric et al., 2003;Staresinic et al., 2003Staresinic et al., , 2006Tudor et al., 2010;Vuksic et al., 2007). BPC 157 also heals hypovascular, hypocellular, and hyponeural tissues (Cerovecki et al., 2010;Chang et al., 2011;Gjurasin et al., 2010;Krivic et al., 2006Krivic et al., , 2008Staresinic et al., 2003). ...

... In a series of acute and chronic injury models, BPC 157 consistently promoted healing after severe injuries in various tissues that were unable to heal spontaneously (Cerovecki et al., 2010;Cesarec et al., 2013;Chang et al., 2011;Gjurasin et al., 2010;Hrelec et al., 2009;Keremi et al., 2009;Klicek et al., 2008;Krivic et al., 2006Krivic et al., , 2008Mikus et al., 2001;Novinscak et al., 2008;Pevec et al., 2010;Sebecic et al., 1999;Seiwerth et al., 1997;Sever et al., 2009;Sikiric et al., 2003;Staresinic et al., 2003Staresinic et al., , 2006Tudor et al., 2010;Vuksic et al., 2007). BPC 157 also heals hypovascular, hypocellular, and hyponeural tissues (Cerovecki et al., 2010;Chang et al., 2011;Gjurasin et al., 2010;Krivic et al., 2006Krivic et al., , 2008Staresinic et al., 2003). ...

... These models might be particularly important, considering that the mechanism of corneal wound healing has not been determined. Further, the effects of BPC 157 alone in wound healing, without any carrier, suggest that they are attributed to its peptidergic activity (Cerovecki et al., 2010;Cesarec et al., 2013;Chang et al., 2011;Gjurasin et al., 2010;Hrelec et al., 2009;Keremi et al., 2009;Klicek et al., 2008;Krivic et al., 2006Krivic et al., , 2008Mikus et al., 2001;Novinscak et al., 2008;Pevec et al., 2010;Sebecic et al., 1999;Seiwerth et al., 1997;Sever et al., 2009;Sikiric et al., 2003;Staresinic et al., 2003Staresinic et al., , 2006Stupnisek et al., 2015;Tudor et al., 2010;Vuksic et al., 2007). BPC 157 also heals hypovascular, hypocellular, and hyponeural tissues (Cerovecki et al., 2010;Chang et al., 2011;Gjurasin et al., 2010;Krivic et al., 2006Krivic et al., , 2008Staresinic et al., 2003).Various types of growth factors mediate corneal wound healing (Imanishi et al., 2000). ...

... Thereby, considering its effects (5-7, 9,15-17), we advocate the stable gastric pentadecapeptide BPC 157 in both inflammatory bowel disease and multiple sclerosis therapy. An additional argument is a direct demonstration of the healing of the severely injured muscles (15)(16)(17) and severely injured nerves (18) and brain injuries (19)(20)(21)(22)(23) not relied on immunomodulation. ...

... No therapy currently exists to repair demyelinated lesions in multiple sclerosis (58). However, besides arguments mentioned before, BPC 157 also provided direct demonstration of the healing of the severely injured muscles (15)(16)(17) and severely injured nerves (18,59) and brain injuries (19-23) not relied on immunomodulation. Whether this approach may be suited to counteract these disabilities in multiple sclerosis patients, remains to be further determined. ...

... Analyzing this study with same dosage regimen used, and the same per-oral protocol, this shows BPC 157's potential to counteract the consequences of the cuprizone application even an extremely high regimen that highly exceeds those commonly applied (62,65). In general, this BPC 157's protocol accords with all protocols used before in studies evidencing BPC 157's healing of the severely injured muscles and severely injured nerves and brain injuries (15)(16)(17)(18)(19)(20)(21)(22)(23)59). ...

Danijela Kolenc

Jelena Suran

Robert Kliček

Predrag Sikiric

Stable gastric pentadecapeptide BPC 157 was suggested to link inflammatory bowel disease and multiple sclerosis, and thereby, shown to equally counteract the models of both of those diseases. For colitis, cysteamine (400 mg/kg intrarectally (1 ml/rat)) and colon-colon anastomosis (sacrifice at day 3, 5, 7, and 14) were used. BPC 157 (10 μg/kg, 10 ng/kg) was applied either intraperitoneally once time daily (first application immediately after surgery, last at 24 hours before sacrifice) or per-orally in drinking water (0.16 μg/ml/12 ml/day till the sacrifice) while controls simultaneously received an equivolume of saline (5 ml/kg) intraperitoneally or drinking water only (12 ml/day). A multiple sclerosis suited toxic rat model, cuprizone (compared with standard, a several times higher regimen, 2.5% of diet regimen + 1 g/kg intragastrically/day) was combined with BPC 157 (in drinking water 0.16 μg or 0.16 ng/ml/12 ml/day/rat + 10 μg or 10 ng/kg intragastrically/day) till the sacrifice at day 4. In general, the controls could not heal cysteamine colitis and colon-colon anastomosis. BPC 157 induced an efficient healing of both at the same time. Likewise, cuprizone-controls clearly exhibited an exaggerated and accelerated damaging process; nerve damage appeared in various brain areas, with most prominent damage in corpus callosum, laterodorsal thalamus, nucleus reunions, anterior horn motor neurons. BPC 157-cuprizone rats had consistently less nerve damage in all damaged areas, especially in those areas that otherwise were most affected. Consistently, BPC 157 counteracted cerebellar ataxia and impaired forelimb function. Thereby, this experimental evidence advocates BPC 157 in both inflammatory bowel disease and multiple sclerosis therapy.

... e., in vitro, in gastric mucosa from rat stomach tissue homogenates, BPC 157, given in the same dose 100 microM as L-arginine, induced a comparable generation of NO [16,17]) and an effect on endothelin serum level [18], BPC 157 protects endothelium (i. e., [2,16,19,20]); counteracts both L-NAME-hypertension and L-arginine-hypotension [16]; exhibits prominent healing angiogenesis (and accelerates VEGF-expression) [21][22][23][24][25][26][27][28][29][30][31][32]; after abdominal aorta anastomosis, BPC 157 application may prevent obstructive thrombus formation and rapidly destroy already formed obstructing thrombus along with the rescuing of lower leg function [20]; as well as after amputation, consistently counteracts aspirin, warfarin and heparin prolonged bleeding [33] as well as thrombocytopenias [33]; and finally, in relation to its response to injury, BPC 157 promotes healing after severe injuries that would otherwise not heal in different tissues, skin [21][22][23], muscle [29][30][31], tendon [28,[34][35][36], ligament [37], nerve [38,39], bone [40,41], gastrointestinal tract [24][25][26][27] and blood vessels [20]. This goes in parallel with the BPC 157 relation with early growth response 1 gene (egr-1)/nerve growth factor 1-A binding protein-2 (naB2), stimulated expression of egr-1 (responsible for cytokine and growth factor generation and early extracellular matrix (collagen) formation) but also its repressor naB2 [42]. ...

... Namely, the wound healing process accomplished all of 4 major events (vascular constriction, loose platelet plug, fibrin mesh to insure stability of platelet plug, dissolution of the clot) that occur in a set order following the loss of vascular integrity, and thereby, not only in theory, an agent implemented in wound healing, and shown to be effective in wound healing (i. e., skin [21][22][23], muscle [29][30][31], tendon [28,[34][35][36], ligament [37], nerve [38,39], bone [40,41], gastrointestinal tract [24][25][26][27] and blood vessels [20]), as it was the case with BPC 157, should be particularly effective in all events after loss of vascular integrity, and thereby, in both developing thrombosis and bleeding disorders [33]. ...

... In support are: the general significance of skeletal muscle for plasma potassium homeostasis, clearly emphasized [113], BPC 157's marked increase of the healing rate of severely damaged skeletal muscles and recovering of their function [29][30][31][32]; hyper/hypokalemia providing the same NO-system evidence (i. e., the same effect of L-NAME/L-arginine in hyper/hypokalemia), and consistent, same BPC 157/NO-system relation in these conditions); BPC 157's heart effects [18,[48][49][50] are along with prominent neuroprotective effect [37,38]. Accordingly, an effect on mictochondrial function could be speculated as well, providing that NO-system controls mitochondrial function [10,11], and that both hypokalemia [123] and hyperkalemia [124] conditions are associated with mitochondirial disturbances. ...

Predrag Sikiric

Sven Seiwerth Rudolf Rucman Bozidar Sebecic

We reviewed stable gastric pentadecapeptide BPC 157-NO-system-relation, its close participation in Moncada's (maintained vascular integrity, platelets control) homeostatic healing response of NO-system to injury. Namely, BPC 157 particular healing effect also affects all events after vascular integrity loss (dependent on circumstances, it reduces either thrombosis (abdominal aorta anastomosis) or bleeding/thrombocytopenia (amputation, heparin, warfarin, aspirin)) and in a series of different injurious models, acute and chronic, BPC 157 consistently advances healing after severe injuries in various tissues spontaneously unable to heal; stimulates egr-1 and naB2 genes; exhibits high safety (LD1 not achieved)). Hypothesis, that BPC 157 (since formed constitutively in the gastric mucosa, stable in human gastric juice, along with significance of NO-synthase and the basal formation of NO in stomach mucosa, greater than that seen in other tissues) exhibits a general, effective competing both with L-arginine analogues (i. e. , L-NAME) and L-arginine, and that this has some physiologic importance (NO-generation), later, practically supports its beneficial effects illustrating BPC 157 and NO-system mutual (with L-NAME/L-arginine; alone and together) relations in (i) gastric mucosa and mucosal protection, following alcohol lesions, in cytoprotection course, NO-generation, and blood pressure regulation; (ii) alcohol acute/chronic intoxication, and withdrawal; (iii) cardiovascular disturbances, chronic heart failure, pulmonary hypertension, and arrhythmias; (iv) disturbances after hypokalemia and hyperkalemia, and potassium-cell membrane dysfunction; and finally, in (v) complex healing failure, proved by the fistulas healing, colocutaneous and esophagocutaneous. However, how this advantage of modulating NO-system (i. e. , particular effect on eNOS gene), may be practically translated into an enhanced clinical performance remains to be determined.

... BPC 157-induced muscle healing implies modulation of the same events; fostering of myocyte regeneration, thus shortening the healing period and avoiding excessive scar formation, again analogous to the preserved muscle/connective tissue ratio in treated rat urethras observed in this study. Additionally, with the same regimens of BPC 157 therapy, along with the previous findings on injured striated muscle [13,14,16], healing effect on peripheral nerve [32], and on smooth muscle of gastrointestinal tract and sphincters [15,17–19], and angiogenesis [30], may be particularly relevant to the noted recovery of the failed LPP in rats after TU and VD. Providing that the procedures used, VD and TU, also directly damaged smooth muscle function, eliminating some of their functions for a while, after GI tract massive resection the remaining part more vigorously adapts in BPC 157 rats, and overwhelms the lack of the removed part [15]. ...

... Considering that pudendal nerve damage is also implicated in SUI pathophysiology, as demonstrated in some other SUI rat model studies (crush, transection) [26], it is important to point out that BPC 157, besides having muscle healing potential [13–19], exhibited significant neuroprotective capabilities [32,34] (e.g., directly improving the transected sciatic nerve healing) [32], thus contributing to regained function after major injury [13,14,16]. Of note, loss of innervations and muscle atrophy [25,35] exists in both VD and TU models as well [25,35]. ...

Ivan Jandric

Hrvoje Vrcic

Marica Jandrić Balen

Predrag Sikiric

Background Since an originally anti-ulcer stable gastric pentadecapeptide BPC 157 (PL 14736) was shown to promote healing of injured striated muscle and smooth muscle in the gastrointestinal tract, we explored its therapeutic potentials for leak point pressure (LPP) recovery in rat stress urinary incontinence (SUI) after transabdominal urethrolysis (TU) and prolonged vaginal dilatation (VD). Material/Methods During a 7-day period, TU-rats and VD-rats (or healthy rats) received BPC 157, either (i) intraperitoneally, 10 μg/kg or 10 ng/kg, once daily (first administration 30 min after surgery, last 24 h before LPP-testing and sacrifice), or (ii) per-orally, 10 μg/kg in drinking water (0.16 μg/mL, 12 mL/rat/day). Vesicourethral segments were harvested for immunohistochemical evaluation. Results All BPC 157 regimens counteracted decrease of LPP values in TU-rats and VD-rats. Additionally, BPC 157-TU rats (μg-intraperitoneally or per-orally) and BPC 157-VD rats (μg intraperitoneally) reached LPP values originally noted in healthy rats. Conversely, in healthy rats, BPC 157 did not alter LPP. Immunohistochemical studies revealed higher desmin (delineates striated organization of skeletal muscle), smooth muscle actin, and CD34 (angiogenic marker) positivity within the urethral wall in BPC 157-treated rats vs. controls, as well as overall preserved muscle/connective tissue ratio assessed with Mallory’s trichrome staining. Conclusions Pentadecapeptide BPC 157, applied parenterally or per-orally, appears to ameliorate the SUI in rat models, improving the otherwise detrimental course of healing after VD and TU, which may be analogous to human injury. These beneficial effects may possibly be selectively used in future strategies for treatment of SUI.

... BPC-157, a human-derived pentadecapeptide, has been shown to exert significant cytoprotective actions in gastrointestinal tissues [11], accelerates wound healing via angiogenesis and collagen formation, and enhances microvascular repair through endothelial nitric oxide synthase (eNOS) -dependent mechanisms across multiple species [12,13,14,15]. By restoring intestinal barrier function and reducing peripheral inflammation, BPC-157 may indirectly preserve BBB integrity and modulate vagal afferent and neurotransmitter signaling, positioning it as a potential bridge between gut and brain homeostasis [16,17,18]. Overall, current evidence supports a model in which BPC-157 coordinates vascular, immune, and neural responses to injury, integrating peripheral mucosal defense with central neuroprotection. ...

... Overall, current evidence supports a model in which BPC-157 coordinates vascular, immune, and neural responses to injury, integrating peripheral mucosal defense with central neuroprotection. However, these conclusions are based almost exclusively on animal studies, and the mechanistic relevance, dose-response relationships, and safety profile in humans remain to be established through rigorous translational and clinical investigation [1,2,3,4,6,8,11,12,13,14,15,16,17,18,19]. ...

Barbara Zofia Pietrzyk

Maciej Waluga

Introduction: The body protection compound-157 (BPC-157) peptide modulates the gut–brain axis (GBA), affecting neural and gastrointestinal functions. Evidence suggests it may promote neuroprotection, regulate inflammation, and influence mood and cognition, with potential clinical relevance for neurodegenerative and psychiatric disorders. This review aimed to comprehensively analyze experimental and clinical data on the biological activity of BPC-157, with a particular focus on its effects on the GBA and its potential therapeutic relevance in neurodegeneration and psychiatric disease. Material and methods: The review authors independently screened and evaluated studies identified through medical databases, including PubMed, Scopus, and institutional repositories. Data extraction and synthesis were conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to ensure methodological transparency and rigor. Results: The collected evidence indicates that BPC-157 exhibits pronounced cytoprotective, anti-inflammatory, and regenerative properties in preclinical models. It enhances neuronal survival, promotes angiogenesis and synaptic plasticity, and modulates key neurotransmitter systems, including dopaminergic, serotonergic, and GABAergic pathways. In animal models, BPC-157 improves motor coordination, cognitive performance, and recovery after neural injury. Preliminary human studies suggest a favorable safety profile, though clinical efficacy data remain limited. Conclusions: BPC-157 demonstrates broad protective and regenerative effects with potential relevance to neurological and psychiatric disorders. Its multimodal action on the GBA highlights a promising therapeutic avenue; however, well-designed clinical trials are required to confirm its efficacy, elucidate mechanisms, and establish optimal dosing strategies.

... Furthermore, there is evidence that BPC 157 counteracted stroke, given in reperfusion, after clamping of the common carotid arteries (i.e., both early and delayed neural hippocampal damage, and achieving full functional recovery (the Morris water maze test, the inclined beam-walking test, and the lateral push test)) (Vukojevic et al., 2020). Likewise, BPC 157 may ameliorate other peripheral and central neuronal damage (Ilic et al., 2009;Ilic et al., 2010;Ilic et al., 2011a;Ilic et al., 2011b;Gjurasin et al., 2010;Tudor et al., 2010;Klicek et al., 2013;Sikiric et al., 2013;Sikiric et al., 2016;Lojo et al., 2016;Drmic et al., 2017;Medvidovic-Grubisic et al., 2017;Perovic et al., 2019;Wang et al., 2019). This may suggest that BPC 157 administration would counteract retinal disturbances also. ...

... Pentadecapeptide BPC 157 (manufactured by Diagen, Ljubljana, Slovenia (Ilic et al., 2009;Ilic et al., 2010;Ilic et al., 2011a;Ilic et al., 2011b;Gjurasin et al., 2010;Tudor et al., 2010;Klicek et al., 2013;Sikiric et al., 2013;Sikiric et al., 2016;Lojo et al., 2016;Drmic et al., 2017;Medvidovic-Grubisic et al., 2017), GEPPPGKPADDAGLV, M.W. 1,419, partial sequence of human gastric juice protein BPC, peptide with 99% high-pressure liquid chromatography (HPLC) purity, expressing 1-des-Gly peptide as an impurity, freely soluble in water at pH 7.0 and in saline) was dissolved in distilled water. L-NAME (Sigma United States) was commercially purchased. ...

Lovorka Batelja Vuletić Mirna Zlatar

Antonio Kokot

Predrag Sikiric

Providing NO-system importance, we suggest that one single application of the NOS-blocker L-NAME may induce retinal ischemia in rats, and that the stable pentadecapeptide BPC 157 may be the therapy, since it may interact with the NO-system and may counteract various adverse effects of L-NAME application. A rat retinal ischemia study was conducted throughout 4 weeks, including fundoscopy, behavior presentation, tonometry, and histology assessment. Retrobulbar L-NAME application (5 mg/kg; 0.5 mg/0.1 ml saline/each eye) in rats immediately produced moderate generalized irregularity in the diameter of blood vessels with moderate atrophy of the optic disc and faint presentation of the choroidal blood vessels, and these lesions rapidly progressed to the severe stage. The specific L-NAME–induced vascular failure points to normal intraocular pressure (except to very transitory increase upon drug retrobulbar administration). When BPC 157 (10 μg; 10 ng/kg, as retrobulbar application, 1 μg; 1 ng/0.1 ml saline/each eye) is given at either 20 min after L-NAME or, lately, at 48 h after L-NAME, the regular retrobulbar L-NAME injection findings disappear. Instead, fundoscopy demonstrated only discrete generalized vessel caliber irregularity with mild atrophy of the optic disc, and then, quite rapidly, normal eye background and choroidal blood vessels, which remain in all of the subsequent periods. Also, histology assessment at 1, 2, and 4 weeks shows that BPC 157 counteracted the damaged inner plexiform layer and inner nuclear layer, and revealed normal retinal thickness. The poor behavioral presentation was also rescued. Thus, while further studies will be done, BPC 157 counteracted L-NAME–induced rat retinal ischemia.

... Also, BPC 157 counteracts the adverse effects of NSAIDs, both COX1 and COX2 inhibitors [7,24,[27][28][29][30][31][32][33][34]. BPC 157 markedly improved rat sciatic nerve healing following nerve transection and/or anastomosis [35]. After an induced traumatic brain injury, there is a marked attenuation of damage with an improved early outcome and minimal postponed mortality throughout a 24 h postinjury period with less intense subarachnoid and intraventricular haemorrhage and brain laceration and subsequent brain oedema considerably improved [36]. ...

... It possibly counteracts lidocaine-induced infiltrative cutaneous analgesia due to its healing effect (thereby causing markedly less oedema and tissue damage after axillary block or after the hot plate test, as BPC 157 prominently heals even severe burns) [75][76][77]. Likewise, in rats with a severed sciatic nerve, BPC 157 markedly improves nerve healing and counteracts autotomy [35], which reflects chronic neuropathic pain, neuroma at the proximal nerve stump, and regenerative nerve sprouts growing into all directions, and prevents or at least significantly attenuates the chain of events otherwise leading to the painful sensation referred to the denervated region [78]. A corresponding autotomy counteraction appears in the L2-L3 spinal compression model, when the stable gastric pentadecapeptide BPC 157 improves the healing course of the spinal cord injury and leads to functional recovery in rats [79]. ...

Marin Lozić

Ivan Krezic

Vasilije Stambolija

Predrag Sikiric

Recently, the pentadecapeptide BPC 157-induced counteraction of bupivacaine cardiotoxicity has been reported. Medication includes (i) lidocaine-induced local anesthesia via intraplantar application and axillary and spinal (L4-L5) intrathecal block, (ii) lidocaine-induced arrhythmias, (iii) convulsions, and (iv) lidocaine-induced HEK293 cell depolarisation. BPC 157 applications (intraplantar, intraperitoneal, and intragastric) were given (i) immediately after lidocaine, (ii) 10 min after, or (iii) 5 min before. The BPC 157/NO-system relationship was verified with NO-agents, the NOS-blocker L-NAME and the NOS-substrate L-arginine, given alone and/or together, in axillary and spinal intrathecal blocks. BPC 157 applied immediately after lidocaine or 5 min before the application of lidocaine considerably ameliorated plantar presentation. BPC 157 medication considerably counteracted lidocaine-induced limb function failure; L-NAME was counteracted; L-arginine exhibited counteraction when given immediately after lidocaine, but prolongation was seen when given later. Given together, prophylactically or therapeutically, L-NAME and L-arginine (L-NAME + L-arginine) counteracted the other’s response. BPC 157 maintained its original response when given together with L-NAME or L-arginine. When BPC 157 was given together with L-NAME and L-arginine, its original response reappeared. BPC 157 antagonised the lidocaine-induced bradycardia and eliminated tonic-clonic convulsions. Also, BPC 157 counteracted the lidocaine-induced depolarisation of HEK293 cells. Thus, BPC 157 has antidote activity in its own right against lidocaine and local anesthetics.

... BPC 157 was recently proposed to be an antagonist of the ethanol (Sikiric et al. 2006(Sikiric et al. , 2010 counteracting both acute and chronic alcohol intoxication (Blagaic et al. 2004;Boban-Blagaic et al. 2006) and these effects were shown to be NO system dependent (Sikiric et al. 2014). In additon, BPC 157 given peripherally, exhibited a number of the beneficial effects on various CNS disturbances (Blagaic et al. 2004;BobanBlagaic et al. 2005BobanBlagaic et al. , 2009Jelovac et al. 1998Jelovac et al. , 1999aSikiric et al. 1999Sikiric et al. , 2000Sikiric et al. , 2001Sikiric et al. , 2002Sikiric et al. , 2011 and nerve injuries (Gjurasin et al. 2010;Tudor et al. 2010), and it might induce the increased release of serotonin in the substantia nigra, acutely and subchronically (Tohyama et al. 2004). This was explained considering a significant pool of BPC 157 from immunohistochemical staining in the stomach and brain (Sikirić et al. 1993;Tohyama et al. 2004).And thereby, although specific evidence is still lacking, it was suggested (Tohyama et al. 2004) that this peptide might also act on the brain's serotonergic system indirectly from a binding site in the gut at some visceral receptive relay (Aziz and Thompson 1998) of the central nervous system. ...

... Also, BPC 157 might counteract the encephalopathies and convulsions that may be induced by overdose of various NSAIDs or insulin Ilic et al. 2009Ilic et al. , 2010Ilic et al. , 2011aSikiric et al. 2013), or those encephalopathies induced by specific neurotoxins, i.e., cuprizone (that mimics multiple sclerosis) . Probably indicatively, BPC 157 has also a neuroprotective effect (Gjurasin et al. 2010;Tudor et al. 2010), and markedly counteracts the unconsciousness after traumatic brain injury (Tudor et al. 2010). ...

Mladen Zemba

Andrea Zemba Čilić

Igor Balenovic

Predrag Sikiric

Aim: We hypothesized that certain effects of the general anaesthetic thiopental are dependent on NO-related mechanisms, which were consequently counteracted by stable gastric pentadecapeptide BPC 157. Main methods: (1) All rats intraperitoneally received thiopental (20, 30, 40, and 50 mg/kg) while medication BPC 157 (10 μg/kg, 10 ng/kg, and 10 pg/kg) was given intraperitoneally at 5 min before thiopental. (2) To determine NO-related mechanisms, all rats received intraperitoneally thiopental 40 mg/kg while BPC 157 (10 μg/kg), L-NAME (10 mg/kg) and L-arginine (30 mg/kg) were applied alone and/or combined. BPC 157 was given at 25 min before thiopental while L-NAME, L-arginine, alone and/or combined, were applied at 20 min before thiopental. Key findings: (1) BPC 157 own effect on thiopental anaesthesia: BPC 157 (10 ng/kg and 10 μg/kg) caused a significant antagonism of general anaesthesia produced by thiopental with a parallel shift of the dose-response curve to the right. (2) L-NAME-L-arginine-BPC 157 interrelations: l -NAME: Thiopental-induced anaesthesia duration was tripled. l-arginine: Usual thiopental anaesthesia time was not influenced. Active only when given with L-NAME or BPC 157: potentiating effects of L-NAME were lessened, not abolished; shortening effect of BPC 157: abolished. BPC 157 and l -NAME: Potentiating effects of L-NAME were abolished. BPC 157 and l -NAME and l-arginine: BPC 157 +L-NAME +L-arginine rats exhibited values close to those in BPC 157 rats. Significance: Thiopental general anaesthesia is simultaneously manipulated in both ways with NO system activity modulation, L-NAME (prolongation) and BPC 157 (shortening/counteraction) and L-arginine (interference with L-NAME and BPC 157).

... Conceptually, to solve this intriguing issue that may involve both the attenuation of the development of thrombosis, obstructive thrombus breakdown and blood vessel function, with counteraction of prolonged bleeding and thrombocytopenia after application of various anticoagulants and anti-platelet agents, we claim that this beneficial effect on bleeding disorders also coincides with BPC 157's wound healing improvement [12,16,19,25,40,42,54,[58][59][60][61]65,66,[94][95][96][97][98][99][100][101][102][103][104][105][106][107]. This beneficial effect was perceived as a brief "repetition" of the agents beneficial efficacy on wound healing acceleration, implicating an effect on vascular constriction, platelet plug stability, fibrin mesh structure and formation which insures the stability of the platelet plug (to counteract the prolonged bleeding and thrombocytopenia after application of various anticoagulants and anti-platelet agents), dissolution of the clot inherent to a successfully exerted wound healing effect (attenuating thrombosis development, breakdown of obstructive thrombus, blood vessel function reestablishing) [10,11]. ...

... This beneficial effect was perceived as a brief "repetition" of the agents beneficial efficacy on wound healing acceleration, implicating an effect on vascular constriction, platelet plug stability, fibrin mesh structure and formation which insures the stability of the platelet plug (to counteract the prolonged bleeding and thrombocytopenia after application of various anticoagulants and anti-platelet agents), dissolution of the clot inherent to a successfully exerted wound healing effect (attenuating thrombosis development, breakdown of obstructive thrombus, blood vessel function reestablishing) [10,11]. It should be noted that BPC 157's "wound healing effect" [1][2][3][4] obviously includes different tissues, skin [12,40,42,94,95], gastrointestinal tract [16,19,25,54,[58][59][60][61]65,66], cornea [96], muscle [97][98][99], tendon [100][101][102], ligament [103], nerve [104,105], blood vessel [10], bone [106,107] (note, chronic BPC 157 application has potent antiinflammatory effects on periodontal tissue in rat periodontitis [107]). It could be likely assumed that this could happen only if all of the 4 major events (vascular constriction, platelet plug stability, fibrin mesh to insure stability of platelet plug, dissolution of the clot) that occur in a set order following the loss of vascular integrity, had been realized, step by step [11]. ...

Predrag Sikiric

Sven Seiwerth Rudolf Rucman Bozidar Sebecic

Stable gastric pentadecapeptide BPC 157 is an anti-ulcer peptidergic agent, proven in clinical trials to be both safe in inflammatory bowel disease (PL-10, PLD-116, PL 14736) and wound healing, stable in human gastric juice, with no toxicity being reported. Recently, we claim that BPC 157 may be used as an antidote against NSAIDs. We focused on BPC 157 beneficial effects on stomach, duodenum, intestine, liver and brain injuries, adjuvant arthritis, pain, hyper/hypothermia, obstructive thrombus formation and thrombolysis, blood vessel function, counteraction of prolonged bleeding and thrombocytopenia after application of various anticoagulants and anti-platelet agents and wound healing improvement. The arguments for BPC 157 antidote activity (i.e., the role of BPC 157 in cytoprotection, being a novel mediator of Roberts cytoprotection and BPC 157 beneficial effects on NSAID mediated lesions in the gastrointestinal tract, liver and brain and finally, counteraction of aspirin-induced prolonged bleeding and thrombocytopenia) obviously have a counteracting effect on several established side-effects of NSAID use. The mentioned variety of the beneficial effects portrayed by BPC 157 may well be a foundation for establishing BPC 157 as a NSAID antidote since no other single agent has portrayed a similar array of effects. Unlike NSAIDs, a very high safety (no reported toxicity (LD1 could be not achieved)) profile is reported for BPC 157. Also, unlike the different dosage levels of aspirin, as a NSAID prototype, which differ by a factor of about ten, all these beneficial and counteracting effects of BPC 157 were obtained using the equipotent dosage (μg, ng/kg) in parenteral or peroral regimens.

... Thus seen from this viewpoint, it is probably more than a coincidence that firstly, BPC 157 has anti-inflammatory effects in the acute, subacute and chronic inflammation models (12), BPC 157 therapy has an effect in preventing and reversing acute pancreatitis, as well as esophagitis (including esophago-jejunal anastomosis-esophagitis), has a particular anti-inflammatory effect modulating inflammatory cells (polymorphonuclearssuppression; mononuclears (attraction) that may be able to reduce local inflammation in bile duct ligation-pancreatitis along with reduced edema and necrosis and reduced serum enzymes values) (1), reduces LTB 4 , TXB 2 , and MPO in serum and inflamed tissues (13,14). Furthermore, BPC 157, could significantly influence afferent nerve function (i.e., as seen in capsaicin studies, it interacts and recovers somatosensory neurons system function, in both adult and new born rats (15) and has likely a neuroprotective effect (16,17). ...

Igor Petrovic Ivan Dobric D Drmic

Predrag Sikiric

Possibly, acute esophagitis and pancreatitis cause each other, and we focused on sphincteric failure as the common causative key able to induce either esophagitis and acute pancreatitis or both of them, and thereby investigate the presence of a common therapy nominator. This may be an anti-ulcer pentadecapeptide BPC 157 (tested for inflammatory bowel disease, wound treatment) affecting esophagitis, lower esophageal and pyloric sphincters failure and acute pancreatitis (10 μg/kg, 10 ng/kg intraperitoneally or in drinking water). The esophagitis-sphincter failure procedure (i.e., insertion of the tubes into the sphincters, lower esophageal and pyloric) and acute pancreatitis procedure (i.e., bile duct ligation) were combined in rats. Esophageal manometry was done in acute pancreatitis patients. In rats acute pancreatitis procedure produced also esophagitis and both sphincter failure, decreased pressure 24 h post-surgery. Furthermore, bile duct ligation alone immediately declines the pressure in both sphincters. Vice versa, the esophagitis-sphincter failure procedure alone produced acute pancreatitis. What's more, these lesions (esophagitis, sphincter failure, acute pancreatitis when combined) aggravate each other (tubes into sphincters and ligated bile duct). Counteraction occurred by BPC 157 therapies. In acute pancreatitis patients lower pressure at rest was in both esophageal sphincters in acute pancreatitis patients. We conclude that BPC 157 could cure esophagitis/sphincter/acute pancreatitis healing failure.

... The number of myelinated nerve fibers has been estimated to decrease after crush injury in rat sciatic nerve [29]. Also, it has been revealed that the diameter [5] and area [4] of the myelinated nerve fibers decrease following sciatic nerve crush (SNC). Sciatic nerve crush leads to inflammatory and oxidative responses [12,15]. ...

... Histological changes, such as decrease in the number and size of myelinated nerve fibers after sciatic nerve crush, have been reported by other researchers [29,5,4]. Our results are in accordance with these findings, in which we demonstrated that the total number, diameter, and area of the myelinated nerve fibers were decreased. ...

Ali Noorafshan

Ameneh Omidi Saeid Karbalay-Doust

The goal of this study was to quantify the histological changes in the dorsal root ganglion (DRG) and the sciatic nerve in rats subjected to sciatic nerve crush (SNC) following curcumin treatment. The rats were divided into four groups, each including five animals, and underwent the following intervention: group I: control animals which received olive oil; group II: sham-operated animals whose skin of the posterior thigh was opened, sutured, and received the vehicle; group III: SNC animals which received the vehicle; and group IV: SNC plus curcumin (100 mg/kg/day) solved in the vehicle. On the 28th day, the fifth lumbar DRG and sciatic nerve were removed. Volume of the ganglion, mean cell volume, total volume of DRG cells (A- and B-cells), and total surface of DRG cells, total number, diameter, and area of the myelinated nerve fibers were estimated using stereological methods. Except for the volume of the ganglion, all other parameters were decreased after nerve crush. In curcumin-treated rats, these parameters decreased, but to a lesser extent, and the values were significantly higher than in the non-treated SNC group (p<0.04). It can be concluded that in rats after crush, curcumin has a protective effect on the DRG and sciatic nerve.

Spomenko Ilic Domagoj Drmic

Kamelija Zarkovic

Predrag Sikiric

We focused on stable gastric pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, MW 1419, an anti-ulcer peptide efficient in inflammatory bowel disease trials (PL 14736), no toxicity reported) because of its hepatoprotective effects. We investigate a particular aspect of the sudden onset of encephalopathy with extreme paracetamol overdose (5 g/kg intraperitoneally) so far not reported: rapidly induced progressive hepatic encephalopathy with generalized convulsions in rats. BPC 157 therapy (10 microg, 10 ng, 10 pg/kg, intraperitoneally or intragastrically) was effective (microg-ng range) against paracetamol toxicity, given in early (BPC 157 immediately after paracetamol, prophylactically) or advanced stage (BPC 157 at 3 hours after paracetamol, therapeutically). At 25 min post-paracetamol increased ALT, AST and ammonium serum values precede liver lesion while in several brain areas, significant damage became apparent, accompanied by generalized convulsions. Through the next 5 hour seizure period and thereafter, the brain damage, liver damage enzyme values and hyperammonemia increased, particularly throughout the 3-24 h post-paracetamol period. BPC 157 demonstrated clinical (no convulsions (prophylactic application) or convulsions rapidly disappeared (therapeutic effect within 25 min)), microscopical (markedly less liver and brain lesions) and biochemical (enzyme and ammonium serum levels decreased) counteraction. Both, the prophylactic and therapeutic benefits (intraperitoneally and intragastrically) clearly imply BPC 157 (microg-ng range) as a highly effective paracetamol antidote even against highly advanced damaging processes induced by an extreme paracetamol over-dose.

... These findings aligned with the Motor Function Recovery and Gastrocnemius Mass Ratio results reported in this study. Previous studies have also reported histopathological changes, using the difference in the morphology of the myelin sheath, axons and myofibrils, following sciatic nerve injury [64,65,66]. Yüce et al [62] reported the derangement of myelin sheath, loss of myelinated fibres and absence of myelin ovoid and cytoskeleton by the end of 7 days, post sciatic nerve crush damage. ...

Thomas Bamidele Akingbade

Simon Ovuakporaye Odomero Thomas Olomo Chukwuemeka Peter Aloamaka

Background: oxidative stress has been established as a significant factor in the pathogenesis of peripheral nerve injury. D-ribose-L-cysteine (DRLC) is an antioxidant agent with central neuroprotective effects. However, it is not known whether DRLC has protective effects on crush sciatic nerve injury. Twenty-five rats were divided into five groups of five rats each. In sham group (G1), the sciatic nerve was exposed but not crushed, whereas in negative control-14 group (G2), negative control-28 (G3), DRLC treated-14 group (G4) and DRLC treated-28 group (G5), the sciatic nerve was exposed and crushed with non-serrated forceps for 30 seconds. Rats in groups G2 and G3 were given normal saline orally, while DRLC (100 mg/kg, orally) was administered to rats in groups G4 and G5 for 14 and 28 straight days respectively. Fourteenth and 28th days post injury, functional recovery was analyzed using a walking track assessment and quantified using the sciatic functional index (SFI), while gastrocnemius atrophic change was evaluated using Gastrocnemius Mass Ratio (GMR), following which all rats were sacrificed, sciatic nerve tissue and gastrocnemius samples were obtained for histopathological evaluation and measurement of Malondialdehyde (MDA), Superoxide Dismutase (SOD) and Catalase (CAT) values. Results: The SFI and GMR scores in groups G2, G3, G4 and G5 were significantly lower than that of G1 group (p<0.05). The SOD values of G2 group, the CAT value of G2 were found to be significantly lower, while MDA value of G2 group was found to be significantly higher, when compared with G1 group respectively (p<0.05). CAT value G5 group showed higher significant difference when compared with G2 group, while MDA value of G5 group was found to be significantly lower than those of G2 and G3 groups (p<0.05). Conclusion: The results indicated that DRLC administered for 28 days, had ameliorative effect on oxidative stress markers, but no restorative effect of DRLC was seen on motor function recovery and gastrocnemius atrophy. Further studies are needed to evaluate the therapeutic effect of DRLC applied in several doses, different administration route and longer duration in crush sciatic nerve injury models.

... Namely, as a part of synchronizing healing (19), BPC 157 accelerates the healing of various wounds (i.e. skin (117)(118)(119), muscle (120)(121)(122)(123)(124)(125), tendon (124)(125)(126)(127)(128), ligament (129), bone (130); corneal ulcers (131) and ulcers in the entire gastrointestinal tract (68,(87)(88)(89)(90)(91)(92)(93)(94)(95)(96)(97)(98), along with external and internal fistulas (12)(13)(14)(15)(16)(17)(18) and anastomosis, intestinal perturbations (95)(96)(97)132), nerve (133) and vascular damage (134). Also, once the peritoneum is damaged, the coagulation cascade is set in motion (135); BPC 157 counteracts the whole Virchow triad (51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63)(64)(65)(66), venous and arterial thrombosis (51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63)(64)(65)(66)134) and attenuates prolonged bleeding and thrombocytopenia after perforation, amputation, and anticoagulant use (35)(36)(37)(82)(83)(84). ...

Darko Vukusić Anita Zenko Sever Marko Sever

Predrag Sikiric

Using duodenocolic fistula in rats, this study attempts to highlight the particular cytoprotection aspects of the healing of fistulas and therapy potential of the stable gastric pentadecapeptide BPC 157, a cytoprotection mediator (i.e. upgrading minor vessels to induce healing at both fistula's sides). Upon duodenocolic fistula creation (two 'perforated' lesions put together) (assessed at 3, 6, 9, 12, and 15 min), BPC 157, given locally at the fistula, or intragastrically (10 μg/kg, 10 ng/kg), rapidly induces vessel 'recruitment', 'running' toward the defect, simultaneously at duodenum and colon, providing numerous collaterals and branching. The mRNA expression studies done at that time provided strongly elevated (nitric oxide synthase 2) and decreased (cyclooxygenase-2, vascular endothelial growth factor A, nitric oxide synthase (NOS)-1, NOS-3, nuclear factor-kappa-B-activating protein) gene expression. As therapy, rats with duodenocolic fistulas, received BPC 157 10 μg/kg, 10 ng/kg, per-orally, in drinking water till sacrifice, or alternatively, intraperitoneally, first application at 30 min after surgery, last at 24 h before sacrifice, at day 1, 3, 7, 14, 21, and 28. Controls exhibited both defects persisting, continuous fistula leakage, diarrhea, continuous weight loss, advanced adhesion formation and intestinal obstruction. Contrary, all BPC 157-treated rats have closed both defects, duodenal and colonic, no fistula leakage (finally, maximal instilled volume corresponds to healthy rats), no cachexia, the same weight as before surgery, no diarrhea, markedly less adhesion formation and intestinal passage obstruction. Thus, BPC 157 regimens resolve the duodenal/colon lesions and duodenocolic fistulas in rats, and rapid vessels recovery appears as the essential point in the implementation of the cytoprotection concept in the fistula therapy.

... The anti-inflammatory activity, capsaicin-induced somatosensory neurons damage counteraction [21], recovery of sciatic nerve after transection [22], and cultured enteric neurons and glial cells protection [23] have been all reported. A particular neuroprotective effect occurred in the therapy of the retinal injury and glaucoma rat models [24,25]. ...

Stjepan Dokuzovic

Darko Perovic Marija Milavic

Predrag Sikiric

Recently, marked therapeutic effects pertaining to the recovery of injured rat spinal cords (1 min compression injury of the sacrocaudal spinal cord (S2-Co1) resulting in tail paralysis) appeared after a single intraperitoneal administration of the stable gastric pentadecapeptide BPC 157 at 10 min post-injury. Besides the demonstrated rapid and sustained recovery (1 year), we showed the particular points of the immediate effect of the BPC 157 therapy that began rapidly after its administration, (i) soon after injury (10 min), or (ii) later (4 days), in the rats with a definitive spinal cord injury. Specifically, in counteracting spinal cord hematoma and swelling, (i) in rats that had undergone acute spinal cord injury, followed by intraperitoneal BPC 157 application at 10 min, we focused on the first 10–30 min post-injury period (assessment of gross, microscopic, and gene expression changes). Taking day 4 post-injury as the definitive injury, (ii) we focused on the immediate effects after the BPC 157 intragastric application over 20 min of the post-therapy period. Comparable long-time recovery was noted in treated rats which had definitive tail paralysis: (iii) the therapy was continuously given per orally in drinking water, beginning at day 4 after injury and lasting one month after injury. BPC 157 rats presented only discrete edema and minimal hemorrhage and increased Nos1, Nos2, and Nos3 values (30 min post-injury, (i)) or only mild hemorrhage, and only discrete vacuolation of tissue (day 4, (ii)). In the day 4–30 post-injury study (iii), BPC 157 rats rapidly presented tail function recovery, and no demyelination process (Luxol fast blue staining).

... BPC-157 has a beneficial effect on muscle healing, with a suggested role in the regeneration of damaged intramuscular nerve branches [23]. BPC-157 also influences the healing of transected rat sciatic nerve [24]. Rivot et al. [25] demonstrated that inflammatory processes in the paw correlate with a spinal increase in nitric oxide (NO) ...

Young-Hoon Jung

Haekyu Kim Hyaejin Kim Hyunjong Kang

Background: The pentadecapeptide BPC-157 has been shown to have anti-inflammatory and wound healing effects on multiple target tissues and organs. Peptides have potent anti-inflammatory effects on periodontal tissues in rats with periodontitis. Few studies have investigated the effect of BPC-157 on pain after dental procedures or oral surgeries. The purpose of the present study was to investigate the antinociceptive effects of BPC-157 on postoperative incisional pain in rats. Methods: Sprague-Dawley rats were randomly divided into five groups: control (saline with the same volume), BPC10 (10 μg/kg of BPC-157), BPC20 (20 μg/kg of BPC-157), BPC40 (40 μg/kg of BPC-157), and morphine (5 mg/kg of morphine). A 1-cm longitudinal incision was made through the skin, fascia, and muscle of the plantar aspect of the hind paw in isoflurane-anesthetised rats. Withdrawal responses were measured using von Frey filaments at 0, 2, 6 h and 4, 7 d after incision. The formalin test was also performed to differentiate its anti-nociceptive effect from an inflammatory reaction or central sensitization. Pain behavior was quantified periodically in phases 1 and 2 by counting the number of flinches in the ipsilateral paw after injection with 30 μL of 5% formalin. Results: The threshold of mechanical allodynia was significantly increased in the BPC10, BPC20, BPC40 and morphine groups compared with that in the control group at 2 h. These increasing thresholds then returned to the levels of the control group. The BPC-157 group showed a much higher threshold at 4 days after incision than the control group. The thresholds of the BPC groups, except the morphine group, were normalized 7 days after incision.The flinching numbers of the BPC10, BPC20, BPC40 and morphine groups were significantly decreased in phase 1, but there was no decrease in the BPC-157 groups except the morphine group in phase 2. Conclusions: BPC-157 was effective only for a short period after incision. It was also effective during phase 1 but not during phase 2, as determined by the formalin test. BPC-157 might have a short antinociceptive effect, even though it has anti-inflammatory and wound healing effects.

... Abrogated venous and arterial thrombosis and recovery of the organ lesions occurred consistently both peripherally and centrally [13]. Furthermore, there is evidence that BPC 157 counteracted stroke, given in reperfusion, after clamping of the common carotid arteries (i.e., both early and delayed neural hippocampal damage and achieving full functional recovery) and ameliorated other central [62][63][64][65][66][67][68][69][70] and peripheral [71] neuronal damage, in particularly those in rats with peripheral or central major vessel occlusion-induced syndromes [7][8][9][10][11][12][13]. This may suggest that, in this way, the neuroprotective effect of BPC 157 administration would also counteract retinal disturbances in glaucomatous disturbances, even with normal intraocular pressure, since BPC 157 might counteract retrobulbar L-NAME application-induced progressive severe atrophy of optic nerve in rats with the normal intraocular pressure [17]. ...

Tamara Kralj

Antonio Kokot Mirna Zlatar

Predrag Sikiric

Cauterization of three episcleral veins (open-angle glaucoma model) induces venous congestion and increases intraocular pressure in rats. If not upgraded, one episcleral vein is regularly unable to acquire and take over the whole function, and glaucoma-like features persist. Recently, the rapid upgrading of the collateral pathways by a stable gastric pentadecapeptide BPC 157 has cured many severe syndromes induced by permanent occlusion of major vessels, veins and/or arteries, peripherally and centrally. In a six-week study, medication was given prophylactically (immediately before glaucoma surgery, i.e., three episcleral veins cauterization) or as curative treatment (starting at 24 h after glaucoma surgery). The daily regimen of BPC 157 (0.4 μg/eye, 0.4 ng/eye; 10 μg/kg, 10 ng/kg) was administered locally as drops in each eye, intraperitoneally (last application at 24 h before sacrifice) or per-orally in drinking water (0.16 μg/mL, 0.16 ng/mL, 12 mL/rat until the sacrifice, first application being intragastric). Consequently, all BPC 157 regimens immediately normalized intraocular pressure. BPC 157-treated rats exhibited normal pupil diameter, microscopically well-preserved ganglion cells and optic nerve presentation, normal fundus presentation, normal retinal and choroidal blood vessel presentation and normal optic nerve presentation. As leading symptoms, increased intraocular pressure and mydriasis, as well as degeneration of retinal ganglion cells, optic nerve head excavation and reduction in optic nerve thickness, generalized severe irregularity of retinal vessels, faint presentation of choroidal vessels and severe optic nerve disc atrophy were all counteracted. In conclusion, we claim that the reversal of the episcleral veins cauterization glaucoma appeared as a consequence of the BPC 157 therapy of the vessel occlusion-induced perilous syndrome.

... Documented consistent healing of the various gastrointestinal fistulas, external (esophagocutaneous, gastrocutaneous, duodenocutaneous, and colocutaneous) [5][6][7][8] and internal (colovesical, rectovaginal) [9,10], was ascribed to its original healing capacity as a peptide native and stable in human gastric juice, and its possible role as novel mediator of Robert's cytoprotection maintaining gastrointestinal mucosal integrity [3], as it is effective in the whole gastrointestinal tract and used in ulcerative colitis clinical trials [1][2][3][4]. Taking fistulas as a pathological connection, and BPC 157 to reestablish original organ function [3], this particular rescue is verified with the beneficial effects in the rats with the various gastrointestinal anastomoses (i.e., esophagogastric [28], jejunoileal [29,30], colo-colonic [31], ileoileal [32], esophagojejunal [33], esophagoduodenal [34], and gastrojejunal [35]) as well as vessel [36] and nerve [37] anastomoses. ...

Domagoj Rasic Anita Zenko Sever Fran Rašić Marko Sever

With the stable gastric pentadecapeptide BPC 157 therapy known to heal various both external and internal rat fistulas, we attempt to approach vesicovaginal fistula, continuous urine leaking through vagina, bladder stones, and a possible therapy solution among rats with well-formed 2 week-fistulas (vaginal/vesical 4 mm large defects) started with delayed therapy. Subsequent control fistula course (the subsequent 1, 2, 4, and 6 weeks) since beginning revealed the failed healing, fistula leaking, adhesions, urinary leaking through vagina, failed epithelization, collagenization, granulation tissue and neovascularization, increased inflammation, and necrosis. Thereby, the later intervals revealed the persistent inability to sustain even minimal volume, vesical, and vaginal defects and stone formation at the end of the experiment (fistula-time day 56). BPC 157 therapy (10 μg/kg, 10 ng/kg, intraperitoneally once time daily or perorally in drinking water until sacrifice) was initiated with a considerable delay (at 2 weeks after fistula formation). Already within 1 week therapy, all BPC 157 regimens stopped urinary leaking through vagina, reversed the otherwise resistant poor healing course to the increased epithelization, collagenization, granulation tissue and neovascularization, decreased inflammation, and decreased necrosis. Thereby, at later intervals, all BPC 157 rats exhibited a five times larger volume that can be sustained before leaking as in healthy, vesical, and vaginal defects completely closed and no stone formation. Thus, macro/microscopic and functional recovery, and counteracted stone formation. Concluding, BPC 157 therapy’s beneficial effects resulted in healing and no stone formation, with μg- and ng-regimens, either given daily perorally in drinking water or intraperitoneally.

... There are counteracted muscle wasting, significantly corrected deranged muscle proliferation as well as myogenesis, counteracted increase of the proinflammatory cytokines such as IL-6 and TNF-α, looking at muscle metabolism relevant to cancer cachexia as well as the changes in the expression of FoxO3a, p-AKT, p-mTOR, and P-GSK-3β (Kang et al., 2018). To illustrate the success of the application and the way of application efficacy, it may be instructive to mention the noted effect in the recovery of the transected sciatic nerve injury (providing the efficacy of the once intraperitoneal, intragastric application much like the application into the tube with inserted nerve stumps) (Gjurasin et al., 2010). In support, recently BPC 157 increased the survival rate of cultured enteric neurons and the proliferation rate of cultured enteric glial cells (Wang et al., 2019). ...

Marija Milavic

Sven Seiwerth

Jaksa Vukojevic

Predrag Sikiric

Significance: The antiulcer peptide, stable gastric pentadecapeptide BPC 157 (previously employed in ulcerative colitis and multiple sclerosis trials, no reported toxicity (LD1 not achieved)), is reviewed, focusing on the particular skin wound therapy, incisional/excisional wound, deep burns, diabetic ulcers, and alkali burns, which may be generalized to the other tissues healing. Recent Advances: BPC 157 has practical applicability (given alone, with the same dose range, and same equipotent routes of application, regardless the injury tested). Critical Issues: By simultaneously curing cutaneous and other tissue wounds (colocutaneous, gastrocutaneous, esophagocutaneous, duodenocutaneous, vesicovaginal, and rectovaginal) in rats, the potency of BPC 157 is evident. Healing of the wounds is accomplished by resolution of vessel constriction, the primary platelet plug, the fibrin mesh which acts to stabilize the platelet plug, and resolution of the clot. Thereby, BPC 157 is effective in wound healing much like it is effective in counteracting bleeding disorders, produced by amputation, and/or anticoagulants application. Likewise, BPC 157 may prevent and/or attenuate or eliminate, thus, counteract both arterial and venous thrombosis. Then, confronted with obstructed vessels, there is circumvention of the occlusion, which may be the particular action of BPC 157 in ischemia/reperfusion. Future Directions: BPC 157 rapidly increases various genes expression in rat excision skin wound. This would define the healing in the other tissues, that is, gastrointestinal tract, tendon, ligament, muscle, bone, nerve, spinal cord, cornea (maintained transparency), and blood vessels, seen with BPC 157 therapy.

... The pentadecapeptide BPC 157 was administered either intraperitoneal, intragastrical, or local at the site of nerve repair in rats and the results showed enhanced functional and histological nerve recovery (Gjurasin et al. 2010). ...

Olimpiu Bota

Lucian Fodor

Currently there are no established adjuvant drugs for the acceleration of peripheral nerve regeneration. In this paper we reviewed the literature from the last 10 years and described the drugs proved to accelerate the functional and histological regeneration of the peripheral nerves, either after trauma or in neuropathy experimental models. The vast majority of the studies were experimental with very few small clinical studies, which indicates the need for prospective randomized studies to identify the best drugs to use as adjuvants for nerve regeneration.

... Furthermore, a wound healing concept (common healing failure considering gastrointestinal ulcers as essential internal unhealed wound vs. healing commonality, gastrointestinal/extra-gastrointestinal healing to be improved) [45,46] in cytoprotection/organoprotection concept would reveal a particular aspect of BPC 157 application [1][2][3][4][5][6][7][8][9][10] in theory and practice. Within the same dose range and routes of application as with gastrointestinal ulcers healing, BPC 157 in wound healing exhibited healing of deep skin burn [47][48][49], transected/injured muscle [50][51][52][53], tendon, ligament [53][54][55][56][57][58] and bone (pseudoarthrosis) [59][60][61], and nerve peripheral and central [62,63], as well as in particular tissues such as cornea [64,65], thought to be related to the endothelium protection [64,65]. Likewise, along with the commonality emphasized in cytoprotection concept appears with BPC 157 application healing of fistulas, otherwise resistant to healing, external [66][67][68][69] and internal [70,71] and healing of the failed anastomoses [72][73][74][75][76], thus, simultaneous healing of dissimilar tissues. ...

Branko Turkovic

Predrag Sikiric Rudolf Rucman

Sven Seiwerth

Years ago, we revealed a novel cytoprotective mediator, stable gastric pentadecapeptide BPC 157, particular anti-ulcer peptide that heals different organs lesions when given as a therapy, native in human gastric juice while maintaining GI- tract mucosal integrity, already tested in trials (ulcerative colitis and now multiple sclerosis). The stomach cytoprotection is the most fundamental concept, stomach cell protection and endothelium protection are largely elaborated, but so far cell, protection and endothelium protection outside of the stomach were not implemented in the therapy. However, having managed these two points, stomach cell protection and endothelium protection, either one or together, even much more than standard cytoprotective agents do, BPC 157 employed large scale of its beneficial effects seen in various organs. Providing endothelium protection, BPC 157 was shown to prevent formation and reverse established thrombosis in anastomosed abdominal aorta as well as venous thrombosis after inferior caval vein occlusion, and attenuate bleeding prolongation and thrombocytopenia after amputation, without or with anticoagulants, or venous occlusion, and finally counteract effect of L-NAME and/or L- arginine. Now, with BPC 157 application, we reveal the third most important part of the cytoprotection concept: with the stomach cell and endothelium protection to recover mucosal integrity, BPC 157 as prototype cytoprotective agent should also control blood vessel function, depending upon injury, perforated defect or vessel obstruction. After a perforated injury (i.e., stomach), BPC 157 therapy activates blood vessels "running" towards defect. After obstruction (i.e., inferior caval vein), BPC 157 activates vessels "running" towards bypassing defect, collaterals functioning. Reestablished blood flow, and largely reversed injurious course may practically implement the cytoprotection concept.

... Significant differences were observed between the trauma groups and the sham group in terms of the myelin sheath thickness, nerve fiber diameter and the numbers of myelinated nerve fibers. Previous studies have also reported histological changes, including in numbers of myelinated nerve fiber numbers and diameters of myelinated nerve fibers, following sciatic nerve damage (30)(31)(32). Yüce et al (2) examined the nerve tissues from rats exposed to crush type nerve damage using electron microscopy and reported the disorganization of myelin, the loss of myelinated fibers and the absence of myelin ovoids and cytoskeleton by the end of week 1. By the end of the week 4, the formation of several thin, myelinated nerve fibers had been reported and the presence of non-myelinated axons was also observed. ...

Sibel Tï¿1⁄2redi Esin Yulug

Ahmet Alver İmran İnce

The present study evaluated the neuroprotective and antioxidant effects of quercetin in a rat model of sciatic nerve crush injury using histopathological, morphometric and biochemical methods. A total of 48 male Sprague Dawley rats, aged 10-12 weeks old were randomly divided into eight groups, consisting of two sham groups (S-7, S-28), three quercetin-treated groups (Q-7, Q-28; 200 mg/kg/7 days), trauma (T-7, T-28; 1 min sciatic nerve crush injury) and three trauma+quercetin groups (T+Q-7, T+Q-28; trauma+quercetin 200 mg/kg/7 days). Rats were sacrificed on day 7 or 28. Oxidant-antioxidant biochemical parameters in nerve tissues from all groups were analyzed using histopathological staining with toluidine blue and Masson’s trichrome. DNA fragmentations were identified using terminal deoxynucleo-tidyl transferase deoxyuridine triphosphate nick-end labeling in cells from each tissue sample. Degeneration of the axons and myelin sheath, the breakdown of the concentric lamellar structure of the myelin sheath and axonal swelling were observed in groups T-7 and T-28. Myelin sheath thicknesses, nerve fiber diameters and the number of myelinated nerve fibers decreased, while the apoptotic index (AI) increased in the T-7 and T-28 groups. However, it was observed that nerve regeneration began in the T+Q-7 and T+Q-28 groups compared with the sham groups, together with the healing of cellular damage and axonal structure and a decrease in the AI. Malondialdehyde and superoxide dismutase activity did not differ significantly between the T-7 and S-7 groups. However, catalase activity significantly decreased in the T-28 group when compared with the sham 7 day group. Tissue malondialdehyde levels significantly increased, while serum catalase activity increased in the T+Q-7 group compared with the T-7 group. These results suggest that quercetin has beneficial effects on nerve regeneration and may shorten the healing period in crush-type sciatic nerve injuries.

... Further, this analogy actually conveys in mentioned NO-system-terms cardiac muscle (decreased extracellular potassium: myocardial hyperexcitability with the potential to develop re-entrant arrhythmias) and skeletal muscle (decreased potassium levels in the extracellular space: hyperpolarization of the resting membrane potential, a greater than normal stimulus for depolarization of the membrane in order to initiate an action potential) [24]. In support, presenting the general significance of skeletal muscle for plasma potassium homeostasis [31], BPC 157's heart effect [9,10,27] are along with prominent neuroprotective effect [33,34], marked increase of the healing rate of severely damaged skeletal muscles and recovering of their function [35][36][37]. ...

... What's more, the premise that when given peripherally, BPC 157 may have a particular beneficial effect on CNS (i.e., markedly less damaged neurons in most severely injuried areas) is in accord with: its neuroprotective properties (34,35), consistent antagonization of different central disturbances (36-39), brain 5-HT synthesis and antagonization of serotonin-syndrome in rats based on region-specific influence on the brain given peripherally either acutely or chronically (i.e., dorsal thalamus, hippocampus, lateral geniculate body, hypothalamus, dorsal raphe nucleus, substantia nigra, medial anterior olfactory nucleus, lateral caudate, accumbens nucleus, superior olive)) (shown by the very precise alpha-[14C]methyl-L-tryptophan (alpha-MTrp) autoradiographic method) (36,40). Presenting the suggested significance of substantia nigra for controlling insulin seizures, it may be important that BPC 157/substantia nigra relation may be particularly substantiated: the increased 5-HT synthesis in substantia nigra was the most prominent one, counteracted 1methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) parkinsonian syndrome as well as the lethal outcome due to particular substantia nigra damage, maintained dopamine system function (BPC 157 may counteract akinesia, catalepsy induced by neuroleptics or reserpine as well as amphetamine-stereotypy behavior) (37)(38)(39). ...

Ilić Spomenko Iva Predrag

We focused on over-dose insulin (250 IU/kg i.p.) induced gastric ulcers and then on other disturbances that were concomitantly induced in rats, seizures (eventually fatal), severely damaged neurons in cerebral cortex and hippocampus, hepatomegaly, fatty liver, increased AST, ALT and amylase serum values, breakdown of liver glycogen with profound hypoglycemia and calcification development. Calcium deposits were present in the blood vessel walls, hepatocytes surrounding blood vessels and sometimes even in parenchyma of the liver mainly as linear and only occasionally as granular accumulation. As an antidote after insulin, we applied the stable gastric pentadecapeptide BPC 157 (10 microg/kg) given (i) intraperitoneally or (ii) intragastrically immediately after insulin. Controls received simultaneously an equivolume of saline (5 ml/kg). Those rats that survived till the 180 minutes after over-dose application were further assessed. Interestingly, pentadecapeptide BPC 157, as an antiulcer peptide, may besides stomach ulcer consistently counteract all insulin disturbances and fatal outcome. BPC 157 rats showed no fatal outcome, they were mostly without hypoglycemic seizures with apparently higher blood glucose levels (glycogen was still present in hepatocytes), less liver pathology (i.e., normal liver weight, less fatty liver), decreased ALT, AST and amylase serum values, markedly less damaged neurons in brain and they only occasionally had small gastric lesions. BPC 157 rats exhibited mostly only dot-like calcium presentation. In conclusion, the success of BPC 157 therapy may indicate a likely role of BPC 157 in insulin controlling and BPC 157 may influence one or more causative process(es) after excessive insulin application.

... In analogy to improve sphincter function, in quadriceps muscle or gastrocnemius muscle complex injuries, BPC 157 increases muscle function and healing, after a complete transection or major crush [67][68][69]. In addition, these effects of BPC 157 [67][68][69] occur concurrently with its marked neuroprotective capability [70,71], and are along with counteracted doxorubicineheart failure and arrhythmias [72,73]. Also, pentadecapeptide BPC 157 given peripherally could affect sphincter function through serotonin [51,74] or dopamine (presenting in the same dose-range BPC 157 prevented/ reversed catalepsy or stereotypy and all concomitant gastrointestinal lesions) [21][22][23][24]. ...

Sven Seiwerth Rudolf Rucman Bozidar Sebecic

Predrag Sikiric

Stable gastric pentadecapeptide BPC 157 is an anti-ulcer peptidergic agent, safe in inflammatory bowel disease clinical trials (GEPPPGKPADDAGLV, M.W. 1419, PL 14736) and wound healing, stable in human gastric juice and has no reported toxicity. We focused on BPC 157 as a therapy in peridontitis, esophagus, stomach, duodenum, intestine, liver and pancreas lesions. Particularly, it has a prominent effect on alcohol-lesions (i.e., acute, chronic) and NSAIDs-lesions (interestingly, BPC 157 both prevents and reverses adjuvant arthritis). In rat esophagitis and failed function of both lower esophageal sphincter (LES) and pyloric sphincters (PS), BPC 157 increased pressure in both sphincters till normal and reduced esophagitis. However, in healthy rats, it may decrease (PS) or increase (LES) the pressure in sphincters. It has strong angiogenic potential, it acts protectively on endothelium, prevents and reverses thrombus formation after abdominal aorta anastomosis, affects many central disturbances (i.e., dopamine and 5-HT system), the NO-system (either L-arginine and L-NAME effects), endothelin, acts as a free radical scavenger (counteracting CCl4-, paracetamol-, diclofenac-injuries) and exhibits neuroprotective properties. BPC 157 successfully heals the intestinal anastomosis, gastrocutaneous, duodenocutaneous and colocutaneous fistulas in rats, as well as interacting with the NO-system. Interestingly, the fistula closure was achieved even when the BPC 157 therapy was postponed for one month. In short-bowel syndrome escalating throughout 4 weeks, the constant weight gain above preoperative values started immediately with peroral and parental BPC 157 therapy and the villus height, crypth depth and muscle thickness (inner (circular) muscular layer) additionally increased. Thus, BPC 157 may improve gastrointestinal tract therapy.

Flynn McGuire Riley Martinez

Annika Lenz

Dan Cushman

Purpose of Review This scoping review aims to evaluate the molecular mechanisms, therapeutic potential, and safety concerns of Body Protective Compound-157 (BPC-157) in the context of musculoskeletal healing. Given the compound’s increasing availability, popularity, and its regulatory controversies, we sought to assess the breadth and quality of preclinical and clinical data supporting its use in musculoskeletal medicine. Recent Findings BPC-157 is a synthetic pentadecapeptide originally isolated from gastric juice and has demonstrated regenerative properties across numerous animal models. It activates several overlapping pathways, notably VEGFR2 and nitric oxide synthesis via the Akt-eNOS axis, promoting angiogenesis, fibroblast activity, and neuromuscular stabilization. It also engages ERK1/2 signaling, facilitates endothelial and muscle repair, and exerts anti-inflammatory effects. These effects promote angiogenesis, fibroblast activity, and neuromuscular stabilization, particularly in poorly vascularized tissues such as tendons and myotendinous junctions. Despite broad preclinical support, human data are extremely limited. Only three pilot studies have examined BPC-157 in humans, including its use for intraarticular knee pain, interstitial cystitis, and intravenous safety/pharmacokinetics. No adverse effects were reported, but rigorous, large-scale trials are lacking. BPC-157 demonstrates robust regenerative and cytoprotective effects in preclinical studies, positioning it as a potentially valuable tool in musculoskeletal medicine. Despite its growing popularity among athletes and its wide availability through non-regulated sources, there is minimal human data available. Until well-designed clinical trials are conducted, BPC-157 should be considered investigational, and its use approached with caution. This review highlights that given the robust preclinical evidence and high public interest, there is a critical need for well-designed human trials to assess the safety, efficacy, and clinical utility of BPC-157 in musculoskeletal medicine.

Anita Skrtic

Predrag Sikiric

Sven Seiwerth Ivan Dobric

Although approached through many concepts, the pleiotropic healing issue, specifically, maintaining/reestablishing tissue integrity, remains a central challenge in pharmacology, particularly when the process is misdirected or not properly controlled. Robert and Szabo’s concept of cytoprotection holds that innate cell (epithelial (Robert), endothelial (Szabo)) integrity and protection/maintenance/reestablishment in the stomach is translated to other organ therapy (cytoprotection → organoprotection) via the cytoprotection agent’s effect. Therefore, we defend stable gastric pentadecapeptide BPC 157 therapy’s efficacy and pleiotropic beneficial effects, along with its high safety (LD1 not achieved), against speculation of its negative impact, speculation of angiogenesis toward tumorigenesis, increased NO and eNOS, damaging free radical formation, and neurodegenerative diseases (Parkinson’s disease and Alzheimer’s disease). Contrarily, in wound healing and general healing capabilities, as reviewed, as a cytoprotective agent and native cytoprotection mediator, BPC 157 controls angiogenesis and the NO-system’s healing functions and counteracts the pathological presentation of neurodegenerative diseases in acknowledged animal models (i.e., Parkinson’s disease and Alzheimer’s disease), and it presents prominent anti-tumor potential in vivo and in vitro. BPC 157 resolved cornea transparency maintenance, cornea healing “angiogenic privilege” (vs. angiogenesis/neovascularization/tumorigenesis), and it does not produce corneal neovascularization but rather opposes it. Per Folkman’s concept, it demonstrates an anti-tumor effect in vivo and in vitro. BPC 157 exhibits a distinctive effect on the NO-level (increase vs. decrease), always combined with the counteraction of free radical formation, and, in mice and rats, BPC 157 therapy counteracts Parkinson’s disease-like and Alzheimer’s disease-like disturbances. Thus, BPC 157 therapy means targeting angiogenesis and NO’s cytotoxic and damaging actions but maintaining, promoting, or recovering their essential protective functions.

Edwin Lee Kailynd Burgess

Background: For years, the peptide Body Protection Compound 157 (BPC-157) has been used to treat partial muscle or tendon tears. Few studies on humans have been published, with none on the intravenous use of BPC-157 in humans. Objective: This IRB-approved study was conducted to assess whether intravenous BPC-157 is safe in humans. Methods: Baseline blood work and vital signs were obtained from 2 participants before and after each infusion. On day 1, 10 mg of BPC-157 in 250 cc of normal saline was infused over one hour. On day 2, fasting blood work was repeated, vital signs were recorded, and 20 mg of BPC-157 in 250 cc of normal saline was infused over one hour. On day 3, fasting blood work and vital signs were repeated. Patients were questioned about any side effects at each appointment. Setting: This study was performed at a private clinic in Florida. Participants: Two patients participated: a 58-year-old Asian male and a 68-year-old Caucasian female, each of whom had received intravenous BPC-157 before this trial. Results: The infusions of BPC-157 resulted in no measurable effects on the tested biomarkers of the heart, liver, kidneys, thyroid, or blood glucose levels. The BPC-157 peptide infusion was tolerated, with no side effects reported. Conclusion: Intravenous infusion of up to 20 mg of BPC-157 in 2 healthy adults showed no adverse effects and was well-tolerated. The results of this pilot study showed the safety of BPC-157 in humans. Future studies are also needed to confirm the safety of intravenous BPC-157 in humans.

Predrag Sikiric Marko Sever

Ivan Krezic

Sven Seiwerth

Since the early 1990s, when Robert’s and Szabo’s cytoprotection concept had already been more than one decade old, but still not implemented in therapy, we suggest the stable gastric pentadecapeptide BPC 157 as the most relevant mediator of the cytoprotection concept. Consequently, it can translate stomach and gastrointestinal mucosal maintenance, epithelium, and endothelium cell protection to the therapy of other tissue healing (organoprotection), easily applicable, as native and stable in human gastric juice for more than 24 h. These overwhelm current clinical evidence (i.e., ulcerative colitis, phase II, no side effects, and no lethal dose (LD1) in toxicology studies), as BPC 157 therapy effectively combined various tissue healing and lesions counteraction. BPC 157 cytoprotection relevance and vascular recovery, activation of collateral pathways, membrane stabilizer, eye therapy, wound healing capability, brain–gut and gut–brain functioning, tumor cachexia counteraction, muscle, tendon, ligament, and bone disturbances counteraction, and the heart disturbances, myocardial infarction, heart failure, pulmonary hypertension, arrhythmias, and thrombosis counteraction appeared in the recent reviews. Here, as concept resolution, we review the counteraction of advanced Virchow triad circumstances by activation of the collateral rescuing pathways, depending on injury, activated azygos vein direct blood flow delivery, to counteract occlusion/occlusion-like syndromes starting with the context of alcohol-stomach lesions. Counteraction of major vessel failure (congested inferior caval vein and superior mesenteric vein, collapsed azygos vein, collapsed abdominal aorta) includes counteraction of the brain (intracerebral and intraventricular hemorrhage), heart (congestion, severe arrhythmias), lung (hemorrhage), and congestion and lesions in the liver, kidney, and gastrointestinal tract, intracranial (superior sagittal sinus), portal and caval hypertension, aortal hypotension, and thrombosis, peripherally and centrally.

Jaksa Vukojevic Marija Milavic

Darko Perovic

Predrag Sikiric

We reviewed the pleiotropic beneficial effects of the stable gastric pentadecapeptide BPC 157, three very recent demonstrations that may be essential in the gut-brain and brain-gut axis operation, and therapy application in the central nervous system disorders, in particular. Firstly, given in the reperfusion, BPC 157 counteracted bilateral clamping of the common carotid arteries-induced stroke, sustained brain neuronal damages were resolved in rats as well as disturbed memory, locomotion, and coordination. This therapy effect supports particular gene expression in hippocampal tissues that appeared in BPC 157-treated rats. Secondly, there are L-NG-nitro arginine methyl ester (L-NAME)-and haloperidol-induced catalepsy as well as the rat acute and chronic models of 'positive-like' schizophrenia symptoms, that BPC 157 counteracted, and resolved the complex relationship of the nitric oxide-system with amphetamine and apomorphine (dopamine agents application), MK-801 (non-competitive antagonist of the N-methyl-D-aspartate receptor) and chronic methamphetamine administration (to induce sensitivity). Thirdly, after rat spinal cord compression, there were advanced healing and functional recovery (counteracted tail paralysis). Likewise, in BPC 157 therapy, there is specific support for each of these topics: counteracted encephalopathies; alleviated vascular occlusion disturbances (stroke); counteracted dopamine disturbances (dopamine receptors blockade, receptors super sensitivity development, or receptor activation, over-release, nigrostriatal damage, vesicles depletion), and nitric oxide-system disturbances ("L-NAME non-responsive, L-arginine responsive," and "L-NAME responsive, L-arginine responsive") (schizophrenia therapy); inflammation reduction, nerve recovery in addition to alleviated hemostasis and vessels function after compression (spinal cord injury therapy). Thus, these disturbances may be all resolved within the same agent's beneficial activity, i.e., the stable gastric pentadecapeptide BPC 157.

Ivan Mirkovic

We focused on the relationship of 0.5% tetracaine-and 0.4% oxybuprocaine-induced corneal anesthesia in rats, and pentadecapeptide BPC 157 (0.4 μg/eye), along with nitric oxide synthase (nOS) inhibitor n(gamma)-nitro-l-arginine methyl ester (l-nAMe) (0.1 mg/eye) and/or nOS substrate l-arginine (2 mg/eye), applied in the form of eye drops. We assessed corneal sensitivity recovery (Cochet-Bonnet esthesiometer), corneal lesion elimination (staining with 10% fluores-cein) and decrease in tear volume (Schirmer test). BPC 157 administration had a full counteracting effect. recovery also occurred in the presence of nOS blockade and nOS substrate application. l-arginine eventually shortened duration of corneal insensitivity and exerted corneal lesion counterac-tion (and counteraction of tetracaine-induced decrease of tear volume) only in earlier but not in later period. l-nAMe application led to longer duration of corneal insensitivity, increase in corneal lesions and decrease in tear volume. When l-nAMe and l-arginine were applied together, they antagonized each other's effect. These distinctions may indicate particular nOS involvement (corneal insensitivity vs. corneal lesion along with tear production), distinctively affected by the administration of nO agents. however, additional BPC 157 co-administration would re-establish counteraction over topical ophthalmic anesthetic-induced effect, be it in its early or late course. We suggest BPC 157 as an antidote to topical ophthalmic anesthetics.

Jaksa Vukojevic

Borna Vrdoljak

Dominik Malekinusic

Predrag Sikiric

Background and purpose We focused on the, yet undescribed, therapy effect of the stable gastric pentadecapeptide BPC 157 in hippocampal ischemia/reperfusion injuries, after bilateral clamping of the common carotid arteries in rats. The background is the proven therapy effect of BPC 157 in ischemia/reperfusion injuries in different tissues. Furthermore, there is the subsequent oxidative stress counteraction, particularly when given during reperfusion. The recovering effect it has on occluded vessels, results with activation of the alternative pathways, bypassing the occlusion in deep vein thrombosis. Finally, the BPC 157 therapy benefits with its proposed role as a novel mediator of Roberts’ cytoprotection and bidirectional effects in the gut‐brain axis. Materials and Methods Male Wistar rats underwent bilateral clamping of the common carotid arteries for a 20‐min period. At 30 s thereafter, we applied medication (BPC 157 10 μg/kg; or saline) as a 1 ml bath directly to the operated area, that is, trigonum caroticum. We documented, in reperfusion, the resolution of the neuronal damages sustained in the brain, resolution of the damages reflected in memory, locomotion, and coordination disturbances, with the presentation of the particular genes expression in hippocampal tissues. Results In the operated rats, at 24 and 72 hr of the reperfusion, the therapy counteracted both early and delayed neural hippocampal damage, achieving full functional recovery (Morris water maze test, inclined beam‐walking test, lateral push test). mRNA expression studies at 1 and 24 hr, provided strongly elevated (Egr1, Akt1, Kras, Src, Foxo, Srf, Vegfr2, Nos3, and Nos1 ) and decreased (Nos2, Nfkb ) gene expression (Mapk1 not activated), as a way how BPC 157 may act. Conclusion Together, these findings suggest that these beneficial BPC 157 effects may provide a novel therapeutic solution for stroke.

Zeljko Djakovic

Ivka Djakovic

Vedran Cesarec

Predrag Sikiric

AIM To cure typically life-threatening esophagogastric anastomosis in rats, lacking anastomosis healing and sphincter function rescue, in particular. METHODS Because we assume esophagogastric fistulas represent a particular NO-system disability, we attempt to identify the benefits of anti-ulcer stable gastric pentadecapeptide BPC 157, which was in trials for ulcerative colitis and currently for multiple sclerosis, in rats with esophagocutaneous fistulas. Previously, BPC 157 therapies have promoted the healing of intestinal anastomosis and fistulas, and esophagitis and gastric lesions, along with rescued sphincter function. Additionally, BPC 157 particularly interacts with the NO-system. In the 4 d after esophagogastric anastomosis creation, rats received medication (/kg intraperitoneally once daily: BPC 157 (10 μg, 10 ng), L-NAME (5 mg), or L-arginine (100 mg) alone and/or combined or BPC 157 (10 μg, 10 ng) in drinking water). For rats underwent esophagogastric anastomosis, daily assessment included progressive stomach damage (sum of the longest diameters, mm), esophagitis (scored 0-5), weak anastomosis (mL H2O before leak), low pressure in esophagus at anastomosis and in the pyloric sphincter (cm H2O), progressive weight loss (g) and mortality. Immediate effect assessed blood vessels disappearance (scored 0-5) at the stomach surface immediately after anastomosis creation. RESULTS BPC 157 (all regimens) fully counteracted the perilous disease course from the very beginning (i.e., with the BPC 157 bath, blood vessels remained present at the gastric surface after anastomosis creation) and eliminated mortality. Additionally, BPC 157 treatment in combination with L-NAME nullified any effect of L-NAME that otherwise intensified the regular course. Consistently, with worsening (with L-NAME administration) and amelioration (with L-arginine), either L-arginine amelioration prevails (attenuated esophageal and gastric lesions) or they counteract each other (L-NAME + L-arginine); with the addition of BPC 157 (L-NAME + L-arginine + BPC 157), there was a marked beneficial effect. BPC 157 treatment for esophagogastric anastomosis, along with NOS-blocker L-NAME and/or NOS substrate L-arginine, demonstrated an innate NO-system disability (as observed with L-arginine effectiveness). BPC 157 distinctively affected corresponding events: worsening (obtained with L-NAME administration that was counteracted); or amelioration (L-arginine + BPC 157-rats correspond to BPC 157-rats). CONCLUSION Innate NO-system disability for esophagogastric anastomoses, including L-NAME-worsening, suggests that these effects could be corrected by L-arginine and almost completely eliminated by BPC 157 therapy.

Vasilije Stambolija Tamara Perleta Stambolija Jadranka Katancic Holjevac

Predrag Sikiric

After the demonstration of its life-saving effect in severe hyperkalemia and the recovery of skeletal muscle after injury, pentadecapeptide BPC 157 has been shown to attenuate the local paralytic effect induced by succinylcholine, in addition to systemic muscle disability (and consequent muscle damage). Hyperkalemia, arrhythmias and a rise in serum enzyme values, were counteracted in rats. Assessments were made at 3 and 30min and 1, 3, 5, and 7 days after succinylcholine administration (1.0mg/kg into the right anterior tibial muscle). BPC 157 (10μg/kg, 10ng/kg) (given intraperitoneally 30min before or immediately after succinylcholine or per-orally in drinking water through 24h until succinylcholine administration) mitigated both local and systemic disturbances. BPC 157 completely eliminated hyperkalemia and arrhythmias, markedly attenuated or erradicated behavioral agitation, muscle twitches, motionless resting and completely eliminated post-succinylcholine hyperalgesia. BPC 157 immediately eliminated leg contractures and counteracted both edema and the decrease in muscle fibers in the diaphragm and injected/non-injected anterior tibial muscles. Therefore, the depolarizing neuromuscular blocker effects of succinylcholine were successfully antagonized.

Rahim Hobbenaghi Javad Javanbakht

Elaheh Shahrokh Hosseini Aghamohammad hassan M

Spinal motoneuron neuroprotection by vitaminB12 was previously reported; the present study was carried out to evaluate neuroprotectivity in the dorsal root ganglion sensory neuron. In present study thirty-six Wister-Albino rats (aged 8–9 weeks and weighing 200–250 g) were tested. The animals were randomly divided into 6 groups which every group contained 6 rats. Group A: received normal saline (for 42 days); Group B: vitamin B12 was administered (0.5 mg/kg/day for 21 days); Group C: received vitamin B12 (1 mg/kg/day for 21days); Group D: received vitamin B12 (0.5 mg/kg/day for 42 days); Group E; received vitamin B12 (1 mg/kg/day for 42 days); Group F; received no treatment. The L5 Dorsal Root Ganglion (DRG) neurons count compared to the number of left and right neurons .Furthermore, DRG sensory neurons for regeneration were evaluated 21 or 42 days after injury (each group was analyzed by One-Way ANOVA test). (1): The comparison of left crushed neurons (LCN) number with right non-crushed neurons in all experimental groups (B, C, D and C), indicating a significant decline in their neurons enumeration (p<0/05). (2): The comparison of test group’s LCN with the control group’s LCN revealed a significant rise in the number of experimental group neurons (p<0/05). (3): Moreover, comparing the number of right neurons in experimental groups with the number of neurons in crushed neurons indicated that the average number of right neurons showed a significant increase in experimental groups (p<0/05). Consequently, the probability of nerve regeneration will be increased by the increment of the administered drug dosage and duration. On the other hand, the regeneration and healing in Dorsal Spinal Ganglion will be improved by increase of administration time and vitamin B12 dose, indicating that such vitamin was able to progress recovery process of peripheral nerves damage in experimental rats. Finally, our results have important implications for elucidating the mechanisms of nerve regeneration. Moreover, the results showed that vitaminB12 had a proliferative effect on the dorsal root ganglion sensory neuron. Virtual slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/7395141841009256

Ivan Barisic Diana Balenovic

Robert Kliček

Predrag Sikiric

We demonstrate the full counteracting ability of stable gastric pentadecapeptide BPC 157 against KCl-overdose (intraperitoneal (i), intragastric (ii), in vitro (iii)), NO-system related. (i) We demonstrated potential (/kg) of: BPC 157 (10ng, 10μg ip, complete counteraction), L-arginine (100mg ip, attenuation) vs. L-NAME (5mg ip, deadly aggravation), given alone and/or combined, before or after intraperitoneal KCl-solution application (9mEq/kg). Therapy was confronted with promptly unrelenting hyperkalemia (>12mmol/L), arrhythmias (and muscular weakness, hypertension, low pressure in lower esophageal and pyloric sphincter) with an ultimate and a regularly inevitable lethal outcome within 30minutes. Previously, we established BPC 157-NO-system interaction; now, a huge life-saving potential. Given 30min before KCl, all BPC 157 regimens regain sinus rhythm, less prolongation of QRS, no asystolic pause. BPC 157 therapy, given 10min after KCl-application, starts the rescue within 5-10minutes, completely restoring normal sinus rhythm at 1h. Likewise, other hyperkalemia-disturbances (muscular weakness, hypertension, low sphincteric pressure) were also counteracted. Accordingly with NO-system relation, deadly aggravation by L-NAME: L-arginine brings to the controls values while BPC 157 always completely nullified lesions, markedly below those of controls. Combined with L-arginine, BPC 157 exhibited no additive effect. (ii) Intragastric KCl-solution application (27mEq/kg)-(hyperkalemia 7mmol/L): severe stomach mucosal lesions, sphincters failure and peaked T waves were fully counteracted by intragastric BPC 157 (10ng, 10μg) application, given 30min before or 10min after KCl. (iii). In HEK293 cells, hyperkalemic conditions (18.6mM potassium concentrations), BPC 157 directly affects potassium conductance, counteracting the effect on membrane potential and depolarizations caused by hyperkalemic conditions.

Masa Hrelec

Robert Kliček

Luka Brcic

Predrag Sikiric

We focused on abdominal aorta, clamped and transected bellow renal arteries, and aortic termino-terminal anastomosis created in Albino male rats. We suggested stomach cytoprotection theory holding endothelium protection and peptidergic anti-ulcer cytoprotection therapy to improve management of abdominal aorta anastomosis and thrombus formation. The stable gastric pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, MW 1419) is a small anti-ulcer peptide efficient in inflammatory bowel disease trials (PL 14736) and various wound treatment, no toxicity reported. After 24 h following aortic termino-terminal anastomosis, we shown that BPC 157 (10 microg/kg) may also decrease formation of cloth after aortic termino-terminal anastomosis and preserved walking ability and muscle strength when given as a bath immediately after aortic anastomosis creation. This may be important since aortic termino-terminal anastomosis is normally presenting in rats with a formed cloth obstructing more than third of aortic lumen, severely impaired walking ability, painful screaming and weak muscle strength. Thereby, the effect of BPC 157 (10 microg/kg) was additionally studied at 24 h following aortic termino-terminal anastomosis. Given at the that point, intraperitoneally, within 3 minutes post-application interval the pentadecapeptide BPC 157 rapidly recovered the function of lower limbs and muscle strength while no cloth could be seen in those rats at the anastomosis site.

Sandra Franjic Spomenko Ilic Domagoj Drmic

Predrag Sikiric

We attempted to fully antagonize the extensive toxicity caused by NSAIDs (using diclofenac as a prototype). Herein, we used the stable gastric pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, MW 1419), an anti-ulcer peptide shown to be efficient in inflammatory bowel disease clinical trials (PL 14736) and various wound treatments with no toxicity reported. This peptide was given to antagonize combined gastrointestinal, liver, and brain toxicity induced by diclofenac (12.5mg/kg intraperitoneally, once daily for 3 days) in rats. Already considered a drug that can reverse the toxic side effects of NSAIDs, BPC 157 (10 μg/kg, 10 ng/kg) was strongly effective throughout the entire experiment when given (i) intraperitoneally immediately after diclofenac or (ii) per-orally in drinking water (0.16 μg/mL, 0.16 ng/mL). Without BPC 157 treatment, at 3h following the last diclofenac challenge, we encountered a complex deleterious circuit of diclofenac toxicity characterized by severe gastric, intestinal and liver lesions, increased bilirubin, aspartate transaminase (AST), alanine transaminase (ALT) serum values, increased liver weight, prolonged sedation/unconsciousness (after any diclofenac challenge) and finally hepatic encephalopathy (brain edema particularly located in the cerebral cortex and cerebellum, more in white than in gray matter, damaged red neurons, particularly in the cerebral cortex and cerebellar nuclei, Purkinje cells and less commonly in the hippocampal neurons). The very extensive antagonization of diclofenac toxicity achieved with BPC 157 (μg-/ng-regimen, intraperitoneally, per-orally) may encourage its further use as a therapy to counteract diclofenac- and other NSAID-induced toxicity.

J Perić

Nikola Jelovac

Predrag Sikiric Rudolf Rucman

A novel gastric pentadecapeptide, BPC 157, has been shown to attenuate different lesions (i.e., gastrointestinal tract, liver, pancreas, somatosensory neurons). This suggests an interaction with the dopamine system. When used alone, BPC 157 does not affect gross behavior or induce stereotypy. We first investigated the effect of pentadecapeptide BPC 157 on stereotypy and acoustic startle response in rats, given as either a prophylactic (10 micrograms/kg i.p.) or therapeutic (10 ng/kg i.p.) regimen, with the dopamine indirect agonist amphetamine (10 mg/kg i.p.). There was a marked attenuation of stereotypic behavior and acoustic startle response. When the medication was given at the time of maximum amphetamine-induced excitability, there was a reversal of this behavior. A further focus was on the effect of this pentadecapeptide on increased climbing behavior in mice pretreated with the dopamine antagonist haloperidol (5.0 mg/kg i.p.), and subsequently treated with amphetamine (20 mg/kg i.p. challenge 1, 2, 4, and 10 days after haloperidol pretreatment). This protocol is usually used for the study of behavioral supersensitivity to the amphetamine stimulating effect. An almost complete reversal was noted when pentadecapeptide was coadministered with haloperidol. Together, these data provide compelling evidence for the interaction of pentadecapeptide BPC 157 with the dopamine system.

Irit Rubinstein

Zaid Abassi R. Coleman

Oma Better

Muscle crush injury is often complicated by hemodynamic shock, electrolyte disorders, and myoglobinuric renal failure. In this study, we examined the involvement of the nitric oxide (NO) system in the development of muscle damage in an experimental model of crush injury induced by exertion of standardized mechanical pressure on tibialis muscle of rat. The intact limb served as a control. Four days after injury, the crushed muscle was characterized by extreme capillary vasodilatation as demonstrated by histological morphometric analysis. These changes were accompanied by muscle hyperperfusion as evaluated by measurements of femoral blood flow (ultrasonic flowmetry) and capillary blood flow (laser-doppler flowmetry). Treatment with Nomega-nitro-L-arginine methyl ester, a NO synthase (NOS) inhibitor, largely decreased the hyperperfusion. Furthermore, the expression of the different NOS isoforms, assessed by reverse transcription-PCR and immunoreactive levels, determined by Western blot, revealed a remarkable induction of the inducible NOS in the crushed limb. Similarly, endothelial NOS mRNA increased gradually after the induction of muscle damage. In contrast, the major muscular NOS, i.e., neuronal isoform remained unchanged. In line with the alterations in the mRNA levels, Western blot analysis revealed parallel changes in the immunoreactive levels of the various NOS. These findings indicate that muscle crush is associated with activation of the NO system mainly due to enhancement of iNOS. This may contribute to NO-dependent extreme vasodilatation in the injured muscle and aggravate the hypovolemic shock after crush injury.

Robert Kliček Marko Sever

Bozo Radic

Predrag Sikiric

We focused on the therapeutic effect of the stable gastric pentadecapeptide BPC 157 and how its action is related to nitric oxide (NO) in persistent colocutaneous fistula in rats (at 5 cm from anus, colon defect of 5 mm, skin defect of 5 mm); this peptide has been shown to be safe in clinical trials for inflammatory bowel disease (PL14736) and safe for intestinal anstomosis therapy. BPC 157 (10 microg/kg, 10 ng/kg) was applied i) in drinking water until the animals were sacrificed at post-operative day 1, 3, 5, 7, 14, 21, and 28; or ii) once daily intraperitoneally (first application 30 min following surgery, last 24 h before sacrifice) alone or with N(G)-nitro-L-arginine methyl ester (L-NAME) (5 mg/kg), L-arginine (200 mg/kg), and their combinations. Sulphasalazine (50 mg/kg) and 6-alpha-methylprednisolone (1 mg/kg) were given once daily intraperitoneally. BPC 157 accelerated parenterally or perorally the healing of colonic and skin defect, leading to the suitable closure of the fistula, macro/microscopically, biomechanically, and functionally (larger water volume sustained without fistula leaking). L-NAME aggravated the healing failure of colocutaneous fistulas, skin, and colon wounds (L-NAME groups). L-Arginine was effective only with blunted NO generation (L-NAME + L-arginine groups) but not without (L-arginine groups). All of the BPC 157 beneficial effects remained unchanged with blunted NO-generation (L-NAME + BPC 157 groups) and with NO substrate (L-arginine + BPC 157 groups) as well as L-NAME and L-arginine co-administration (L-NAME + L-arginine + BPC 157 groups). Sulphasalazine was only moderately effective, and corticosteroid even had an aggravating effect.

Luka Brcic

Tomislav Novinscak

Staresinic Mario

Predrag Sikiric

Stable gastric pentadecapeptide BPC 157 accelerates the healing of a transected Achilles tendon and a transected quadriceps muscle. It may also be of clinical relevance as a systemic and local peptide treatment for crush injury of a major muscle, such as gastrocnemius muscle complex. BPC 157 is effective without a carrier, and it is presently undergoing trials for inflammatory bowel disease, and no toxicity has so far been reported. In crushed rats (force delivered 0.727 Ns/cm2), BPC 157 was applied either intraperitoneally or locally, as a thin cream layer, immediately after injury (sacrifice at 2 h), and once a day for 14 days. BPC 157 improved muscle healing, macroscopically (less hematoma and edema, no post-injury leg contracture), microscopically, functionally, and also based on enzyme activity (creatine kinase, lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase). BPC 157, at all investigated intervals, given locally or intraperitoneally, accelerated post-injury muscle healing and also helped to restore the full function.

Katoh KK

Toni Storm Bruce G. Gold

The axonal regenerative properties of the new immunosuppressant drug FK506 (tacrolimus) are further explored in this continuing study. In an initial report (Gold et al., 1994a), we described the ability of FK506 to reduce the time until return of function in the hind feet of rats following a sciatic nerve crush. In the present study, we examined the morphological correlate underlying this enhancement of functional recovery. In rats receiving daily subcutaneous injections of FK506 (1.0 mg/kg) for 18 d following a sciatic nerve crush the regenerating axons appeared larger in size compared to saline-injected control animals. Morphometric analysis of axonal calibers in the soleus nerve demonstrated that mean axonal areas for the largest 30% of axons were increased over axotomized control values by 93% in the FK506-treated animals. Next, the rate of axonal regeneration was determined by radiolabeling the L5 dorsal root ganglion (DRG) at 9 and 14 d following axotomy. Regression analysis of the outgrowth distances for sensory axons between 10 and 15 d revealed a 16% increase in regeneration rate. Electron microscopy of intramuscular nerve branches in the interosseus muscles confirmed that the axons in the FK506-treated animals were further advanced toward their targets; in some instances, axons were shown to reinnervate muscle spindles. The results are discussed in terms of the known ability of FK506 to inhibit the activity protein phosphatase 2B (calcineurin).

Martina Lovric Bencic Jadranka Šeparović Hanževački

Predrag Sikiric

Alenka Boban Blagaic

Overall, doxorubicine-congestive heart failure (CHF) (male Wistar rats and NMRI mice; 6 challenges with doxorubicine (2.5 mg/kg, i.p.) throughout 15 days and then a 4-week-rest period) is consistently deteriorating throughout next 14 days, if not reversed or ameliorated by therapy (/kg per day): a stable gastric pentadecapeptide BPC157 (GEPPPGKPADDAGLV, MW 1419, promisingly studied for inflammatory bowel disease (Pliva; PL 10, PLD-116, PL 14736)) (10 microg, 10 ng), losartan (0.7 mg), amlodipine (0.07 mg), given intragastrically (i.g.) (once daily, rats) or in drinking water (mice). Assessed were big endothelin-1 (BET-1) and plasma enzyme levels (CK, MBCK, LDH, AST, ALT) before and after 14 days of therapy and clinical status (hypotension, increased heart rate and respiratory rate, and ascites) every 2 days. Controls (distilled water (5 ml/kg, i.g., once daily) or drinking water (2 ml/mouse per day) given throughout 14 days) exhibited additionally increased BET-1 and aggravated clinical status, while enzyme values maintained their initial increase. BPC157 (10 microg/kg) and amlodipine treatment reversed the increased BET-1 (rats, mice), AST, ALT, CK (rats, mice), and LDH (mice) values. BPC157 (10 ng/kg) and losartan opposed further increase of BET-1 (rats, mice). Losartan reduces AST, ALT, CK, and LDH serum values. BPC157 (10 ng/kg) reduces AST and ALT serum values. Clinical status of CHF-rats and -mice is accordingly improved by the BPC157 regimens and amlodipine.

Yoshihiro Tohyama

Mirko Diksic

Predrag Sikiric

A novel pentadecapeptide, BPC157, was recently reported to have a large spectrum of in vivo activities, from anti-ulcer to central action on the brain dopaminergic system. The mechanisms of these actions are not well understood. In this study, the evaluation of the effects of acute and repeated administration of BPC157 on serotonin (5-HT) synthesis in the rat brain is reported. The alpha-[14C]methyl-L-tryptophan (alpha-MTrp) autoradiographic method was used to measure regional 5-HT synthesis rates. In the first series of experiments, a single dose treatment of BPC157 (10 microg/kg) administered intraperitoneally 40 min before the alpha-MTrp tracer injection significantly reduced the regional rate of 5-HT synthesis in the dorsal thalamus, hippocampus, lateral geniculate body and hypothalamus. 5-HT synthesis rates in the substantia nigra reticulate and medial anterior olfactory nucleus in BPC157 treated rats were significantly higher than in the control rats. No significant change in the synthesis rate was observed in the raphe nuclei. In the second series of experiments, following a 7-day treatment with BPC157 (10 microg/kg; s.c.), a significant reduction in the 5-HT synthesis rate was observed in the dorsal raphe nucleus, and significant increases were observed in the substantia nigra, lateral caudate, accumbens nucleus and superior olive. This data suggests that BPC157, a gut peptide, influences brain 5-HT synthesis in rats, but we cannot determine, from this data, the mechanism of this action.

Dasa seveljevic-jaran

Miroslava Dominis Kramaric

Snjezana Cuzic

Michael Parnham

PL 14736 is a synthetic peptide, originally isolated from human gastric juice, that has anti-inflammatory and tissue-protective actions in experimental models of gastrointestinal inflammation. To investigate its possible benefit in poorly healing skin wounds, the effects of the topical application of PL 14736 in a gel formulation have been studied on full-thickness excisional wounds in rats, either healthy or made hyperglycemic by alloxan (175 mg/kg s.c.) 5 days previously. The effects of becaplermin gel (platelet-derived growth factor, PDGF-BB, Regranex, a standard therapy for diabetic foot ulcers, were investigated for comparison. Healing was evaluated for up to 7 days after wounding, using digital planimetry analysis, macroscopic scoring and histology. While healing was too rapid in healthy rats to observe enhancement by either treatment, in the hyperglycemic rats which exhibited delayed healing, PL 14736 (10-1,000 microg/wound) produced a dose-dependent acceleration of wound healing (determined by macroscopic scoring) equivalent at the highest doses to that observed with becaplermin. The beneficial effect on healing was associated with increased deposition of organized granulation tissue by day 7 for both PL 14736 and becaplermin, as determined histologically. PL 14736 tended to have a greater effect than becaplermin on the formation of granulation tissue containing mature collagen. Wound contraction, as measured by planimetry, was not significantly affected. In conclusion, topical PL 14736 produces a dose-dependent acceleration of deficient skin wound healing in hyperglycemic rats by facilitating granulation tissue formation, similar to the response seen with topical becaplermin, the standard therapy for diabetic skin wounds. PL 14736 may represent an alternative therapy for delayed wound healing, such as that seen with diabetic foot ulcers, without the proliferative concerns or immunogenicity associated with growth factors.

Andrija Krivic Mate Majerović I Jelić

Predrag Sikiric

In the presented study we compared the effect of stable peptide BPC 157 and methylprednisolone on early functional recovery after Achilles tendon to bone transection in a rat model before collagen healing started. Surgical transection of the right Achilles tendon to bone area was performed in seventy two Wistar Albino male rats. Healing Achilles tendon edges were harvested at days 1-4 following the transection. Using Achilles functional index (AFI), myeloperoxidase activity, histological inflammatory cell influx and vascular index early functional recovery was evaluated. Agents (stable peptide BPC 157 10 microg methylprednisolone 5 mg, normal saline 5 ml) were given alone (/kg b.w., intraperitoneally, once daily, first 30 min after surgery, last 24 h before analysis). Control group received normal saline 5 ml/kg. BPC 157 improved functional recovery (AFI values increased at all time points, p <0.05) by anti-inflammatory (decreased myeloperoxidase (MPO) activity and histological inflammatory cell influx, p <0.05) and increased new blood vessel formation (increased vascular index, p <0.05). Methyprednisolone decreased MPO activity and histological inflammatory cell influx, (p <0.05) but also decreased new blood vessel formation and did not affect early functional recovery. Stable peptide BPC 157 with combined anti-inflammatory action and induction of early new blood vessel formation facilitates early functional recovery in Achilles tendon to bone healing.

Arnaud Bocquet

Geneviève Lorent Bruno Fuks

Henrik Klitgaard

The aim of this study was to evaluate the neurotrophic and neuroprotective properties of a series of immunophilin ligands and to assess the potential involvement of FK506 Binding Protein 12 kDa (FKBP12) rotamase inhibition in this activity. Both FK506 and rapamycin induced a potent inhibition of the FKBP12 rotamase activity (pIC50 values of 7.3 and 7.4, respectively) but only a modest inhibition was observed with 1-(3,3-dimethyl-2-oxo-pentanoyl)-pyrrolidine-2-carboxylic acid S-3-pyridin-3-yl-propyl ester (GPI 1046) (5.8), its N-oxide (5.4) and thioester (6.3) analogues. Compared to nerve growth factor, all these immunophilin ligands only induced marginal increases in neurite outgrowth of rat dissociated newborn dorsal root ganglia cells. Furthermore, systemic administration of GPI 1046 and its N-oxide and thioester analogues failed to prevent striatal dopamine depletion induced by acute or chronic i.p. treatment with 1-methyl-4-phenyl 1,2,3,6 tetrahydropyridine (MPTP). These results suggest that inhibition of FKBP12 rotamase activity is not predictive for neurotrophic and neuroprotective properties of immunophilin ligands and question their therapeutic utility in neurodegenerative diseases like Parkinson's disease.

Manfred Zimmermann

This review deals with physiological and biological mechanisms of neuropathic pain, that is, pain induced by injury or disease of the nervous system. Animal models of neuropathic pain mostly use injury to a peripheral nerve, therefore, our focus is on results from nerve injury models. To make sure that the nerve injury models are related to pain, the behavior was assessed of animals following nerve injury, i.e. partial/total nerve transection/ligation or chronic nerve constriction. The following behaviors observed in such animals are considered to indicate pain: (a) autotomy, i.e. self-attack, assessed by counting the number of wounds implied, (b) hyperalgesia, i.e. strong withdrawal responses to a moderate heat stimulus, (c) allodynia, i.e. withdrawal in response to non-noxious tactile or cold stimuli. These behavioral parameters have been exploited to study the pharmacology and modulation of neuropathic pain. Nerve fibers develop abnormal ectopic excitability at or near the site of nerve injury. The

Danira Pevec

Tomislav Novinscak

Luka Brcic

Predrag Sikiric

The effect of systemic and local peptide treatment effective in muscle contusion and then on counteraction of corticosteroid-induced impairment was tested. The pentadecapeptide BPC 157, given without a carrier, improved the healing of transected quadriceps muscle. It also improved muscle healing in rats with muscle crush injury when applied systemically or locally. Importantly, it counteracted corticosteroid-impairment in tendon to bone healing. Thus BPC 157 is proposed as an effective treatment that can improve muscle healing in spite of corticosteroid treatment. After the gastrocnemius muscle complex had been injured, rats received BPC 157 (intraperitoneally or locally as a cream) and/or 6alpha-methylprednisolone (intraperitoneally) only once (immediately after injury, sacrifice at 2 h) or once daily (final dose 24 hours before sacrifice and/or assessment procedure at days 1, 2, 4, 7, and 14). Muscle healing was evaluated functionally, macroscopically, and histologically. Without therapy, crushed gastrocnemius muscle complex controls showed limited improvement. 6alpha-methylprednisolone markedly aggravated healing. In contrast, BPC 157 induced faster muscle healing and full function restoration and improved muscle healing despite systemic corticosteroid treatment when given intraperitoneally or locally and demonstrated functionally, macroscopically, and histologically at all investigated intervals. BPC 157 completely reversed systemic corticosteroid-impaired muscle healing.

Dijana Balenovic

Martina Lovric Bencic

Mario Udovicic

Predrag Sikiric

Pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, MW 1419) reversed congestive heart failure and various arrhythmias, influenced the NO-system and showed no proarrhythmic effect. In therapy analogy, we challenged rats with digitalis, to show attenuation by BPC 157 and the relation between the NO-system and digitalis toxicity. (i). BPC 157 prophylactic effect. Development of cumulative intravenous digitalis toxicity, BPC 157 (50 microg, 10 microg, 10 ng/kg applied intravenously immediately before a methyldigoxin increment regimen (2.0/1.5/1.5/1.0 mg/kg at 15 min-intervals, total dose 6.0 mg/kg/45 min)) reduced the number of ventricular premature beats, prolonged the time before onset of ventricular tachycardia, reduced ventricular tachycardia and AV-block duration (microg-regimes) or reduced mainly the AV-block duration (ng-regimen). (ii). BPC 157 therapy. Advanced methyldigoxin toxicity (6.0 mg/kg i.v. bolus). BPC 157 applied at the 20th second of the grade 3 AV-block shortened AV-blocks, mitigated a further digitalis toxicity course. Ventricular tachycardias were either avoided (50 microg), or markedly reduced (10 microg, 10 ng). Fatal outcome was either avoided (50 microg), reduced (10 microg), or only delayed (10 ng) (iii) BPC 157, L-NAME, l-arginine, L-NAME+l-arginine application. L-NAME-application (5 mg/kg i.p.) aggravated methyldigoxin-arrhythmias. l-arginine (200 mg/kg i.p.) alone had no effect but blunted L-NAME-exaggeration (L-NAME+l-arginine). In this respect, BPC 157 (50 microg/kg i.p.) was prophylactically and therapeutically more effective: the antagonism of L-NAME with BPC 157 produced an effect similar to BPC 157 alone. In conclusion, digitalis-induced arrhythmias in rats could be prevented and counteracted by pentadecapeptide BPC 157, mainly through an interaction with the NO-system.

Patrick D. Wall

Marshall Devor Rivka Inbal M M Tomkiewicz

(1) When hindlimb peripheral nerves are cut across in rats and mice, there is a tendency for the animal to attack the anaesthetic limb. We have called this attack "autotomy". In this paper we describe the time course and degree of autotomy following various types of nerve injury. (2) Four different types of lesion were applied to the sciatic nerve of rats. The most serious autotomy was produced by section of the nerve and encapsulation of its cut end in a polythene tube. Section followed by immediate resuturing also produced serious autotomy. Simple ligation of the nerve end was followed by less autotomy than encapsulation or cut and resuture. A crush lesion caused only minimal attack. (3) Section of the saphenous branch of the femoral nerve produced no autotomy. However, if the saphenous and sciatic nerves were ligated at the same time so that the entire foot became anaesthetic there was a great increase of autotomy over that seen when the sciatic nerve alone was ligated. This increase with the double lesion occurred even if the saphenous nerve was ligated more than 100 days after the sciatic nerve had been cut. (4) Mice showed autotomy very similar to that seen in rats but the onset was somewhat faster. (5) Reasons are given to propose that autotomy is triggered by an abnormal afferent barrage generated in the cut end of the nerve. Autotomy from peripheral nerve lesions is a different phenomenon from that seen after dorsal root section. Autotomy occurs under conditions which produce anaesthesia dolorosa in man. This simple model may be suitable for studies of the prevention of irritations originating from chronic lesions of peripheral nerves.

L McDevitt P Fortner Bruce Pomeranz

Direct current (DC) electrical stimulation of the hindpaw is shown to enhance sciatic motor nerve regeneration in the adult rat. Cathodal stimulation, using weak currents (10 microA/cm2; field strength approximately 100 mV/cm) increased the reinnervation of the hindpaw muscles as measured by evoked electromyograms. This enhanced regeneration only occurred after cut-and-suture lesions, but not after crushing injury of the sciatic nerve. This enhancement of motor nerve regeneration by weak DC fields had been previously described in amphibians but we are the first to describe this phenomenon in mammals.

Predrag Sikiric

Sven Seiwerth

Zeljko Grabarevic

Anton Marović

Very recently, the integrity of capsaicin somatosensory neurons and their protection were suggested to be related to the activity in nociception of a newly discovered 15-amino acid peptide, BPC 157, shown to have strong beneficial effect on intestinal and liver lesions. Therefore, from this viewpoint, we have studied the gastroprotective effect of the pentadecapeptide BPC 157, on gastric lesions produced in rats by 96% ethanol, restraint stress, and indomethacin. The possible involvement of sensory neurons in the salutary actions of BPC 157 (10 micrograms/kg, 10 ng/kg intraperitoneally) was studied with capsaicin, which has differential effects on sensory neurons: a high dose in adult (125 mg/kg subcutaneously, 3 months old) or administration (50 mg/kg subcutaneously) to neonatal animals (age of the 7 days) destroys sensory fibers, whereas a low dose (500 micrograms/kg intraperitoneally) activates neurotransmitter release and protective effects on the mucosa. In the absence of capsaicin, BPC 157 protected gastric mucosa against ethanol, restraint, and indomethacin application. In the presence of neurotoxic doses of capsaicin, the negative influence of capsaicin on restraint, ethanol, or indomethacin lesions consistently affected salutary activity of BPC 157. However, BPC 157 protection was still evident in the capsaicin-treated rats (either treated as adults or as newborns) in all of these assays. Interestingly, after neonatal capsaicin treatment, a complete abolition of BPC gastroprotection was noted if BPC 157 was applied as a single nanogram-regimen, but the mucosal protection was fully reversed when the same dose was used daily. In line with the excitatory dose of capsaicin the beneficial effectiveness of BPC 157 appears to be increased as well. Taken together, these data provide evidence for complex synergistic interaction between the beneficial effectiveness of BPC 157 and peptidergic sensory afferent neuron activity.

Hiroshi Asada Yuzo Yamaguchi Sigeru Tsunoda Yutaka Fukuda

A model of deafferentation pain is provided by sectioning the sciatic and saphenous nerves in the rat and mouse. This procedure leads to self-mutilation of the denervated hindpaw (autotomy). A noxious stimulus to the denervated area before neurectomy is known to enhance the autotomy. To understand the mechanism underlying this enhancement by prior noxious stimuli, we examined the effects of intrathecal (i.t.) injection of substance P (SP) and somatostatin (SOM) on autotomy behavior. These peptides are known to be released from primary afferent terminals in the dorsal horn by noxious stimuli. A single i.t. injection of SP or SOM just before neurectomy dramatically enhanced autotomy behavior in mice. Autotomy was enhanced in a dose-dependent manner with i.t. injection of SP (0.1-20 nmol) 5 min before neurectomy or SOM (0.1-1.0 nmol) 20 min before neurectomy. Autotomy significantly decreased by extending the interval between i.t. injection of SP or SOM and neurectomy. Intact mice injected with the same doses of SP or SOM showed dose-dependent acute nociceptive responses directed to the hindpaw. The severity of autotomy in neurectomized mice and the duration of acute nociceptive responses induced by the same doses of SP or SOM in intact mice were related. These results suggest that neuropeptides applied to the spinal dorsal horn just before deafferentation induce a state of central neural activation with long-lasting effects on the function of CNS cells. Augmentation of autotomy is a result of this activation which is kept as a 'memory'.

Costantino Iadecola

There is increasing evidence that nitric oxide (NO), a free radical that can act both as a signaling molecule and a neurotoxin, is involved in the mechanisms of cerebral ischemia. Although early investigations yielded conflicting results, the introduction of more-selective pharmacological tools and the use of molecular approaches for deletion of genes encoding for NO synthase have provided a better understanding of the role of NO in the mechanisms of ischemic brain damage. The evidence reviewed in this article suggests that NO is protective or destructive depending on the stage of evolution of the ischemic process and on the cellular source of NO. Defining the role of NO in cerebral ischemia provides the rationale for new neuroprotective strategies based on modulation of NO production in the post-ischemic brain.

Min-Sheng Wang Michelle Zeleny-Pooley Bruce G. Gold

The new immunosuppressant drug FK506 (Tacrolimus) increases the rate of nerve regeneration in vivo (Gold et al., 1994; Gold et al., 1995). In the present study, we have examined the dose-dependence of FK506's ability to enhance nerve regeneration. In the first set of experiments, rats received daily s.c. injections of FK506 (2 mg/kg, 5 mg/kg or 10 mg/kg) for 18 days after a sciatic nerve crush injury. Signs of functional recovery in the hind feet appeared earlier than in saline-treated control rats at all three FK506 dosage; recovery was maximally accelerated in the 5-mg/kg group. Light microscopy at 18 days after nerve crush revealed more regenerating myelinated fibers in FK506-treated rats than in controls; this was most apparent in the 5-mg/kg group. Morphometric analysis of axonal areas in the soleus nerve confirmed that axonal calibers were maximally increased in the 5-mg/kg group. In the second set of experiments, the rate of axonal regeneration was determined by radiolabeling the L5 dorsal root ganglion. Regeneration rate for sensory axons was maximally increased (by 34%) in the 5-mg/kg group. In contrast, cyclosporin A (10 or 50 mg/kg; dosages were selected on the basis of the 1/10 lower potency of cyclosporin A) did not significantly alter the rate of axonal regeneration. Cyclosporin A (50 mg/kg) also failed to increase functional recovery or axonal calibers in the soleus nerve. Because the two drugs share a common mechanism for producing immunosuppression (i.e., calcineurin inhibition), these results indicate that FK506's nerve regenerative property involves a distinct, calcineurin-independent mechanism.

Predrag Sikiric

Sven Seiwerth

Zeljko Grabarevic

Anton Marović

The known effects of a novel stomach pentadecapeptide BPC157 (10 microg or 10 ng/kg), namely its salutary activity against ethanol (96%, i.g.)-induced gastric lesions (simultaneously applied i.p.) and in blood pressure maintenance (given i.v.), were investigated in rats challenged with a combination of N(G)-nitro-L-arginine methylester (L-NAME) (5 mg/kg i.v.), a competitive inhibitor of endothelium nitric oxide (NO)-generation and NO precursor, L-arginine (200 mg/kg i.v.) (D-arginine was ineffective). In the gastric lesions assay, NO agents were given 5 min before ethanol injury and BPC 157 medication. Given alone, BPC157 had an antiulcer effect, as did L-arginine, but L-NAME had no effect. L-NAME completely abolished the effect of L-arginine, whereas it only attenuated the effect of BPC 157. After application of the combination of L-NAME + L-arginine, the BPC157 effect was additionally impaired. In blood pressure studies, compared with L-arginine, pentadecapeptide BPC 157 (without effect on basal normal values) had both a mimicking effect (impaired L-NAME-blood pressure increase, when applied prophylactically and decreased already raised L-NAME values, given at the time of the maximal L-NAME-blood pressure increase (i.e., 10 min after L-NAME)) and preventive activity (L-arginine-induced moderate blood pressure decrease was prevented by BPC 157 pretreatment). When BPC 157 was given 10 min after L-NAME + L-arginine combination, which still led to a blood pressure increase, its previously clear effect (noted in L-NAME treated rats) disappeared. In vitro, in gastric mucosa from rat stomach tissue homogenates, BPC 157, given in the same dose (100 microM) as L-arginine, induced a comparable generation of NO. But, BPC 157 effect could not be inhibited by L-NAME, even when L-NAME was given in a tenfold (100 versus 1000 microM) higher dose than that needed for inhibition of the L-arginine effect. NO synthesis was blunted when the pentadecapeptide BPC 157 and L-arginine were combined. In summary, BPC 157 could interfere with the effects of NO on both gastric mucosal integrity and blood pressure maintenance in a specific way, especially with L-arginine, having a more prominent and/or particularly different effect from that of NO.

Zeljko Grabarevic Z Kolega

Sven Seiwerth

Predrag Sikiric

The 15 amino acid agent BPC 157, showing a wide range of organoprotective action in different experimental models, was used in our experiments in order to establish its influence on different elements connected with the healing process. Elements thought to be of greatest importance in the process of healing are formation of granulation tissue, angiogenesis and production of collagen. In our work we tested the influence of BPC 157 on: granulation tissue and collagen formation, on angiogenesis as well as on tensile strength development, using three experimental rat models: 1) skin incisional wounds; 2) colon-colon anastomoses; and 3) angiogenesis model with synthetic sponge implantation. The specimens were histologically assessed for collagen, reticulin and blood vessels using scoring and morphometry. In all experiments significant differences between BPC 157-treated animals and controls were found, showing a strong, promoting involvement of BPC in the healing process. It is worth noting that these effects were achieved by different routes of application, including intragastric and local, making BPC 157 a potentially useful therapeutic agent.

Stefan Frank Marianne Madlener Josef Pfeilschifter Sabine Werner

Recent work has suggested a possible role of nitric oxide, a free radical gas, during the wound healing process. In this study we investigated the regulation of inducible nitric oxide synthase (iNOS) and GTP-cyclohydrolase I (GTP-CH I), the rate-limiting enzyme in the biosynthesis of the iNOS cofactor (6R) 5,6,7,8-tetrahydrobiopterin (6-BH4), during the repair process. We found a similar time course of induction of iNOS and GTP-CH I expression, whereas absolute expression levels were different for both genes. Immunohistochemical analysis revealed colocalization of iNOS and GTP-CH I proteins in the wound. Systemic treatment with glucocorticoids significantly altered the expression levels of iNOS and GTP-CH I. Expression of iNOS and GTP-CH I was suppressed by glucocorticoids in normal, and to a much greater extent in wounded skin. Furthermore, a role of nitric oxide as a novel mediator of gene regulation during healing is suggested by the demonstration of nitric oxide-mediated induction of vascular endothelial growth factor expression in keratinocytes. These findings may provide an explanation for the beneficial effects of orally supplemented L-arginine on wound healing, and suggest that a disturbed induction of iNOS and GTP-CH I expression may at least partially underlie the wound healing defect seen in glucocorticoid-treated animals.

Joseph R Madsen Paul MacDonald

Nina Irwin

Larry Benowitz

Tacrolimus (FK506), a widely used immunosuppressant drug, has neurite-promoting activity in cultured PC12 cells and peripheral neurons. The present study investigated whether tacrolimus affects the expression of the neuronal growth-associated protein, GAP-43, as well as functional recovery after photothrombotic spinal cord injury in the rat. In injured animals receiving tacrolimus, the number of neurons expressing GAP-43 mRNA and protein approximately doubled compared to that in injured animals receiving vehicle alone. This increase in GAP-43-positive cells was paralleled by a significant improvement in neurological function evaluated by open-field and inclined plane tests. Another FKBP-12 ligand (V-10,367) had similar effects on GAP-43 expression and functional outcome, indicating that the observed effects of tacrolimus do not involve inhibition of the phosphatase calcineurin. Thus, tacrolimus, a drug which is already approved for use in humans, as well as other FKBP-12 ligands which do not inhibit calcineurin, could potentially enhance functional outcome after CNS injury in humans.

G Keilhoff

Silke Altmann W Schneider

Hisham Fansa

Nerve allografts are highly antigenic and require the continuous use of immunosuppressive drugs. Neurotoxic complications from immunosuppressant therapy with FK 506 have been noted in the central and peripheral nervous system although an increased rate of axonal regeneration has also been noted. Regeneration of peripheral nerve grafts was assessed in a rat model clinically and morphometrically after treatment for 2 and 6 weeks with two different doses of FK 506. Good regeneration was noted in all groups at 6 weeks. A significantly higher axon count was observed in both the FK 506 groups after 2 weeks regeneration compared with controls. This beneficial effect was not evident after 6 weeks of regeneration. Whether this is related to a pruning mechanism or to a down-regulation of regenerative processes in the nerve due to possible neurotoxic effects of FK 506 remains unknown.

Nikola Jelovac Rudolf Rucman

Ingrid Prkacin

Predrag Sikiric

A gastric pentadecapeptide, BPC 157, with the amino acid sequence, Gly-Glu-Pro-Pro-Pro-Gly-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-Val, MW 1419, known to have a variety of protective effects in gastrointestinal tract and other organs, was recently shown to particularly affect dopamine systems. For instance, it blocks the stereotypy produced acutely by amphetamine in rats, and the development of haloperidol-induced supersensitivity to amphetamine in mice. Consequently, whether pentadecapeptide BPC 157, that by itself has no cataleptogenic effect in normal animals, may attenuate the immediate effects of neuroleptics application, particularly catalepsy, was the focus of the present report. Prominent catalepsy, otherwise consistently seen in the mice treated with haloperidol (0.625, 1.25, 2.5, 5.0 and 10.0 mg/kg b.w., i.p.) and fluphenazine (0.3125, 0.625, 1.25, 2.5 and 5.0 mg/kg b.w., i.p.) after 1.5, 3, 4.5, 6 and 7.5 h following administration, was markedly attenuated when pentadecapeptide BPC 157 (10 microg or 10 ng/kg b.w., i.p.) was coadministered with the neuroleptic. The number of cataleptic mice was markedly lower throughout most of the experimental period. Moreover, on challenge with lower doses of neuroleptics, catalepsy appearance was postponed and the mice, otherwise cataleptic since the earliest period, became cataleptic later, not before 3 or 4.5 h after neuroleptic administration, especially if protected with higher pentadecapeptide dose. Besides catalepsy, coadministration of the pentadecapeptide BPC 157, given in the above mentioned doses, reduced not only catalepsy but somatosensory disorientation (for 7.5 h after administration of a neuroleptic, assessed at intervals of 1.5 h, by a simple scoring system [0-5]) in haloperidol- or fluphenazine-challenged mice as it did in mice treated with sulpiride (20, 40, 80 and 160 mg/kg b.w., i.p.) or with clozapine (25, 50 and 100 mg/kg b.w., i.p.), in which case catalepsy was absent. In other experiments, considering the gastric origin of this pentadecapeptide, the focus was shifted to the evidence that a dose of haloperidol, cataleptogenic due to dopamine receptors blockade, induces gastric ulcers in rats. Coadministration of pentadecapeptide BPC 157 (10 microg, 10 ng, 1.0 ng, 100 pg/kg b.w., i.p.) to rats completely inhibited the lesions otherwise regularly evident 24 h after haloperidol (5.0 mg/kg b.w., i.p.) in control rats (18 of 20 rats had gastric lesions). This activity accompanied the antagonism of the haloperidol catalepsy in rats (assessed at 60-min intervals from I to 5 h after haloperidol), when 10-microg- or 10-ng regimens were given (lower doses could not influence catalepsy). Together, these findings indicate that pentadecapeptide BPC 157 fully interacts with the dopamine system, both centrally and peripherally, or at least, that BPC 157 interferes with some steps involved in catalepsy and/or ulcer formation.

Anton Marović Wendy Matoz Vladimir Hahn

Predrag Sikiric

The effect of a stomach pentadecapeptide, BPC 157, on Parkinson's disease in mice was investigated, along with its salutary activity on stomach lesions induced by parkinsongenic agents. Parkinsongenic agents, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (30.0 mg x kg(-1)b.w. i.p. once daily for 6d, and after 4d once 50.0 mg x kg(-1)b.w. i.p.) or reserpine (5.0 mg x kg(-1)b.w. i.p.) were applied i.p. BPC 157 (1.50 microg or 15.0 ng x kg(-1)b.w. i.p.) was applied 15 min before or alternatively 15 min after each MPTP administration. In reserpine studies, BPC 157 (10.0 microg or 10.0 ng x kg(-1)b.w. i.p.) was given either 15 min before reserpine or in the already established complete catalepsy 24 h thereafter. BPC 157 strongly improved the MPTP-impaired somatosensory orientation and reduced the MPTP-induced hyperactivity, and most importantly, MPTP-motor abnormalities (tremor, akinesia, catalepsy -otherwise very prominent in saline control), leading to almost complete abolition of otherwise regularly lethal course of MPTP treatment in controls. Likewise, in reserpine experiments, BPC 157 strongly prevented the development of otherwise very prominent catalepsy and when applied 24 h thereafter reversed the established catalepsy. In addition, a reduction of reserpine-hypothermy (BPC 157 pre-treatment) and reversal of further prominent temperature fall (BPC 157 post-treatment) have been consistently observed. Taking together these data, as the two most suitable animal models were consistently used and since the high effectiveness was demonstrated in pre- and post-treatment, microg and ng regimens, BPC 157 as an organoprotector should be further therapeutically investigated. Additionally, given in either regimen, pentadecapeptide BPC 157 strongly attenuated the stomach lesions in mice that otherwise consistently appeared in mice treated with the parkinsogenic neurotoxin MPTP.

Jadranka Separovic Ivo Rotkvić

Predrag Sikiric Tomislav Anic

A clear protection of the gastrointestinal tract and an evident anti-inflammatory effect were shown for a novel stomach pentadecapeptide BPC 157 (i.p./i.g.) in comparison with several reference standards in various ulcer models along with a protection of endothelium and particular interaction with the NO-system. Thus, we evaluated whether this pentadecapeptide along with other gastroprotective agents could affect angiogenesis and the healing process in vivo using a procedure initially described by Szabo and co-workers. In each rat, two sterile sponges (1 x 1 x 0.25 cm; V = 0.25 mL) with the same quantities of BPC 157 (10 ng x mL(-1), 10 microg x mL(-1), 50 microg x kg(-1)) or reference agents (cimetidine: 10, 100, 500 mg x mL(-1); ranitidine: 2.5, 25, 250 mg x mL(-1); famotidine: 10, 50, 100 mg x mL(-1); omeprazole: 10, 50, 100 mg x mL(-1); sucralfate: 1, 5, 10 mg x mL(-1) were implanted subcutaneously in the lumbar region. The sponges were removed after 3 or 7 d, fixed in formalin, and processed for histologic and histochemical evaluation and morphometry assessment. Compared with the control values, the number of newly formed endothelial spaces inside newly formed granulation tissue was markedly increased in all animals treated with BPC 157, cimetidine, ranitidine, famotidine, sucralfate and omeprazole, a consistent finding noted after either 3 or 7 d. Compared with control values, markedly more granulation tissue was noted in the rats in the groups of animals treated with BPC 157 (50 microg) and in the rats treated with sucralfate in all dosages used, euthanized after 3 d. In all groups treated with H2-blockers however, similar values to those of controls were noted. Thus, it could be concluded that an evident angiogenic property was consistently noted for the novel pentadecapeptide BPC 157, H2-blockers (cimetidine, famotidine and ranitidine) and omeprazole, besides the well known angiogenic effect of sucralfate. Furthermore, unlike H2-blockers and omeprazole, BPC 157 stimulates the formation of granulation tissue, suggesting a particular activity, similar to that previously noted for sucralfate.

Bruce G. Gold

Neuroimmunophilin ligands are a class of compounds that hold great promise for the treatment of nerve injuries and neurological disease. In contrast to neurotrophins (e.g., nerve growth factor), these compounds readily cross the blood-brain barrier, being orally effective in a variety of animal models of ischaemia, traumatic nerve injury and human neurodegenerative disorders. A further distinction is that neuroimmunophilin ligands act via unique receptors that are unrelated to the classical neurotrophic receptors (e.g., trk), making it unlikely that clinical trials will encounter the same difficulties found with the neurotrophins. Another advantage is that two neuroimmunophilin ligands (cyclosporin A and FK-506) have already been used in humans (as immunosuppressant drugs). Whereas both cyclosporin A and FK-506 demonstrate neuroprotective actions, only FK-506 and its derivatives have been clearly shown to exhibit significant neuroregenerative activity. Accordingly, the neuroprotective and neuroregenerative properties seem to arise via different mechanisms. Furthermore, the neuroregenerative property does not involve calcineurin inhibition (essential for immunosuppression). This is important since most of the limiting side effects produced by these drugs arise via calcineurin inhibition. A major breakthrough for the development of this class of compounds for the treatment of human neurological disorders was the ability to separate the neuroregenerative property of FK-506 from its immunosuppressant action via the development of non-immunosuppressant (non-calcineurin inhibiting) derivatives. Further studies revealed that different receptor subtypes, or FK-506-binding proteins (FKBPs), mediate immunosuppression and nerve regeneration (FKBP-12 and FKBP-52, respectively, the latter being a component of steroid receptor complexes). Thus, steroid receptor chaperone proteins represent novel targets for future drug development of novel classes of compounds for the treatment of a variety of human neurological disorders, including traumatic injury (e.g., peripheral nerve and spinal cord), chemical exposure (e.g., vinca alkaloids, Taxol) and neurodegenerative disease (e.g. , diabetic neuropathy and Parkinson's disease).

Xavier Navarro

Esther Udina Dolores Ceballos Bruce G. Gold

We compared the effects of FK506 administration on regeneration and reinnervation after sciatic nerve resection and repair with an autologous graft or with a silicone tube leaving a 6-mm gap in the mouse. Functional reinnervation was assessed by noninvasive methods to determine recovery of motor, sensory, and sweating functions in the hindpaw over 4 months after operation. Morphometric analysis of the regenerated nerves was performed at the end of follow-up. The nerve graft allowed for faster and higher levels of reinnervation in the four functions tested than silicone tube repair. Treatment with FK506 (for the first 9 weeks only) resulted in a slight, although not significant, improvement of the onset of reinnervation and of the maximal degree of recovery achieved after autografting. The recovery of pain sensibility and of the compound nerve action potentials in the digital nerves, which directly depend on axonal regeneration, showed better progression with FK506 than reinnervation of muscles and sweat glands, which require reestablishment of synaptic contacts with target cells. The myelinated fibers in the regenerated nerve showed a more mature appearance in the FK506-treated rats. However, FK506 showed a marginal effect in situations in which regeneration was limited, as in a silicone tube bridging a 6-mm gap in the mouse sciatic nerve. In conclusion, treatment with FK506 improved the rate of functional recovery after nerve resection and autograft repair.

Darko Mikus

Predrag Sikiric

Sven Seiwerth Tomislav Anic

The effects of the gastric pentadecapeptide BPC 157 were investigated when administered topically or systemically in burned mice. This agent is known to have a beneficial effect in a variety of models of gastrointestinal lesions, as well as on wound or fracture healing. Deep partial skin thickness burns (1.5x1.5 cm) covering 20% of total body area, were induced under anesthesia on the back of mice by controlled burning and gastric lesions were assessed 1, 2, 3, 7, 14 and 21 days following injury. The first application of BPC 157 was immediately following burning, and thereafter, once daily, until 24 h before sacrifice. In the initial experiments, exposure to direct flame for 5 s, the BPC 157 was applied at 10 microg or 10 ng/kg b.w. intraperitoneally (i.p.) by injection or alternatively, topically, at the burn, as a thin layer of cream (50 microg of BPC 157 dissolved in 2 ml of distilled water was mixed with 50 g of commercial neutral cream (also used as local vehicle-control)), while silver sulfadiazine 1% cream was a standard agent acting locally. Others received no local medication: they were treated i.p. by injection of distilled water (distilled water-control) or left without any medication (control). In subsequent experiments involving deeper burns (direct flame for 7 s), BPC 157 creams (50 microg, 5 microg, 500 ng, 50 ng or 5 ng of BPC 157 dissolved in 2 ml of distilled water was mixed with 50 g of commercial neutral cream), or vehicle as a thin layer of cream, were applied topically, at the burn. Compared with untreated controls, in both experiments, in the BPC 157 cream-treated mice all parameters of burn healing were improved throughout the experiment: less edema was observed and inflammatory cell numbers decreased. Less necrosis was seen with an increased number of capillaries along with an advanced formation of dermal reticulin and collagen fibers. An increased number of preserved follicles were observed. Two weeks after injury, BPC 157 cream-treated mice completely reversed the otherwise poor re-epithelization ratio noted in the untreated control or mice treated with vehicle only. Tensiometry investigation showed an increased breaking strength and relative elongation of burned skin, while water content in burned skin decreased. This was, however, not the case with the vehicle or silver sulfadiazine. Relative to the control values, in silver sulfadiazine cream-treated mice, only collagen fiber formation was increased, in addition to a decreased inflammatory cell number. Relative to control values, BPC 157 given i.p. decreased the number of inflammatory cells, lowered water content in burned skin, and raised breaking strength and relative elongation of burned skin during tensiometry. Through the experimental period, gastric lesions were continuously noted in all thermally injured mice left without local medication and they were consistently attenuated only by BPC 157 treatments: either given i.p. (at either dose), or given locally (at either concentration). Other treatments (i.e. local treatment with silver sulfadiazine cream or neutral cream in mice subjected for 5 s to direct flame), led to only poor, if any attenuation. This stable gastric pentadecapeptide appears to be active and gives a stimulation to burn healing at the defect site. The agent may act by causing an upregulation of the growth factors, as well as influencing other local factors.

J. Gordon Boyd

Tessa Gordon

The time-dependent decline in the ability of motoneurons to regenerate their axons after axotomy is one of the principle contributing factors to poor functional recovery after peripheral nerve injury. A decline in neurotrophic support may be partially responsible for this effect. The up-regulation of BDNF after injury, both in denervated Schwann cells and in axotomized motoneurons, suggests its importance in motor axonal regeneration. In adult female Sprague-Dawley rats, we counted the number of freshly injured or chronically axotomized tibial motoneurons that had regenerated their axons 1 month after surgical suture to a freshly denervated common peroneal distal nerve stump. Motor axonal regeneration was evaluated by applying fluorescent retrograde neurotracers to the common peroneal nerve 20 mm distal to the injury site and counting the number of fluorescently labelled motoneurons in the T11-L1 region of the spinal cord. We report that low doses of BDNF (0.5-2 microg/day for 28 days) had no detectable effect on axonal regeneration after immediate nerve repair, but promoted axonal regeneration of motoneurons whose regenerative capacity was reduced by chronic axotomy 2 months prior to nerve resuture, completely reversing the negative effects of delayed nerve repair. In contrast, high doses of BDNF (12-20 microg/day for 28 days) significantly inhibited motor axonal regeneration, after both immediate nerve repair and nerve repair after chronic axotomy. The inhibitory actions of high dose BDNF could be reversed by functional blockade of p75 receptors, thus implicating these receptors as mediators of the inhibitory effects of high dose exogenous BDNF.

Charles S. Day Boonsin Buranapanitkit

Felix Riano

Johnny Huard

Despite modern microsurgical techniques for nerve repair, functional outcome following proximal injury is often unsatisfactory because irreversible muscle atrophy may develop before reinnervation occurs. Because insulin growth factor-1 (IGF-1) has been shown to improve muscle regeneration after injury, and may have a role in muscle preservation following denervation, the purpose of this investigation was to evaluate the histological, immunohistochemical, and electrophysiological differences between normal, denervated, and IGF-1-injected denervated muscle over an 8-week period. Denervated mice gastrocnemius muscles demonstrated a decrease in muscle weight, a decrease in myofiber diameter, an absence of muscle regeneration, an early increase in the number of neuromuscular junctions (NMJs), and a decrease in fast-twitch and maximum tetanic strength as compared to normal muscle up to 8 weeks following denervation. IGF-1-injected denervated muscle, on the other hand, sustained muscle diameter and muscle weight, maintained a smaller number of NMJs, and relatively sustained fast-twitch and maximum tetanic strength as compared to normal muscle over 8 weeks. These data suggest that IGF-1 may help prevent muscle atrophy and secondary functional compromise after denervation.

Hisham Fansa

Gerburg Keilhoff

Thomas F.W. Horn Wolfgang Schneider

PURPOSE: Nerve allografts are highly antigenic and, thus, require the continuous use of immunosuppressive drugs. FK 506 was found to pre-vent rejection successfully. However, clinically neurotoxic complications have been noted in the central and peripheral nervous system although an increased rate of axonal regeneration has also been shown after nerve crush experiments. To investigate whether a possible regeneration pro-moting potency of FK 506 is determined via an influence on Schwann cells, Schwann cells were cultured from the sciatic nerve of the rat. METHODS: The effect of 100 micro M FK 506 administered daily on these cultures was assessed microscopically over a period of seven days and compared to an untreated control group of cultures. Additionally, the changes in intracellular calcium were recorded using a laser scanning microscope. In vivo regeneration of autologous rat sciatic nerve grafts was assessed clinically, histologically and morphometrically after two and six weeks. The animals received a daily administration of 0.6 mg FK 506/kg body weight, the control received saline. RESULTS: In vitro FK 506 increased the Schwann cell number in culture significantly compared to non treated cultures, while the fibrocyte population was decreased. FK 506 caused a transient increase of intracellular calcium levels in cultured cells. In vivo, a significantly higher axon count was observed in the FK 506 treated grafts after two weeks regeneration compared with controls. Good regeneration was noted in all grafts after six weeks regeneration. CONCLUSIONS: The increased axon counts and decreased myelin debris in the FK 506 grafts after two weeks indicate an accelerated Wallerian degeneration and increased axon sprouting into the graft initially. The inhibition of calcineurin activity is not the mediator of the neurotrophic effect. FK 506 promotes axonal regeneration through binding to FKBP-12. The increase of intracellular calcium may induce Schwann cell pro-liferation via calmodulin. The therapeutic relevance for autologous nerve grafting, however, has to be defined in further studies.

Marie Jubran

Johan Widenfalk

Peripheral nerve injury is often followed by incomplete recovery of function and sometimes associated with neuropathic pain. There is, therefore, need for therapies which improve the speed of recovery and the final functional outcome after peripheral nerve injuries. In addition, neuropathic pain is not easily dealt with clinically and should preferably be eliminated. Neurotrophic factors have well-documented abilities to support neuron survival and stimulate neurite outgrowth, making them excellent candidates for use in repairing injured nerves. We investigated the possible beneficial effects of repairing the transected rat sciatic nerve by local application of a fibrin sealant containing nerve growth factor (NGF), glial cell line-derived neurotrophic factor (GDNF), or acidic fibroblast growth factor (aFGF). Fibrin sealant was used in conjunction with sutures. Evaluation of motor and sensory function, autotomy, and histological parameters was carried out from 1 to 12 weeks after injury. We demonstrate that NGF cotreatment decreased the occurance of autotomy, suggesting a reduction of neuropathic pain, and improved the performance in motor and sensory tests. In addition, the number of regenerating motoneurons was significantly increased after NGF administration. GDNF increased the speed of sensory recovery, but also markedly increased autotomy, indicating an increased degree of neuropathic pain. aFGF did not alter the outcome of the motor or sensory tests. Fibrin sealant could easily be used in conjunction with sutures to deliver neurotrophic substances locally to the damaged nerve and to enhance recovery of nerve function.

S Mise

Predrag Sikiric

Sven Seiwerth Tomislav Anic

The amelioration of corticosteroid-impairment of healing by a stable gastric pentadecapeptide BPC-157 (GEPPPGKPADDAGLV, M(w) 1419, currently in early clinical trials for inflammatory bowel disease) was studied in thermally injured mice. Its effects on corticosteroid impaired healing of deep partial skin thickness burns, and burn-gastric lesions were investigated. Male NMRI-Hannover mice (sacrificed at 1-3,7,14 and 21 days following burning 20% of total burn area at the back (open flame for 7s) received intraperitoneally (per kg bw) 6alpha-methylprednisolone (Depo-medrol, 1.0 or 10.0mg), or an equal volume of saline (5.0 ml), once daily, first application 30 min after injury, last 24h before sacrifice. The injury was subsequently treated by topical application of a thin layer of pentadecapeptide BPC-157 cream at three different levels a neutral cream of no treatment. Pentadecapeptide BPC-157 consistently improved given burn healing (both microscopical and tensionmetry assessment), and counteracted corticosteroid-impairment of burn healing. In burn-gastric lesions investigation of the effects of BPC showed an anti-ulcer effect of its own in burned non-corticosteroid-treated mice and potentiated the anti-ulcer effect observed in 6alpha-methylprednisolone-treated mice. Pentadecapeptide BPC-157 inhibited corticosteroid immunosuppression. In vitro, in spleenic cells assessment, animals (sacrificed at day 21) treated with 6alpha-methylprednisolone 1mg showed decreased reactivity to nitrogen in comparison with control, healthy animals, while the addition of BPC-157 (1 microg/g cream) returned cell reactivity to values noted in control healthy animals.

Bozidar Sebecic

Leonardo Patrlj

Staresinic Mario

Predrag Sikiric

In studies intended to improve healing of transected Achilles tendon, effective was a stable gastric pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, M.W. 1419). Currently in clinical trials for inflammatory bowel disease (PLD-116, PL 14736, Pliva), it ameliorates internal and external wound healing. In rats, the right Achilles tendon transected (5 mm proximal to its calcaneal insertion) presents with a large tendon defect between cut ends. Agents (/kg b.w., i.p., once time daily) (BPC 157 (dissolved in saline, with no carrier addition) (10 microg, 10 ng or 10 pg) or saline (5.0 ml)), were firstly applied at 30 min after surgery, the last application at 24 h before autopsy. Achilles functional index (AFI) was assessed once time daily. Biomechanical, microscopical and macroscopical assessment was on day 1, 4, 7, 10 and 14. Controls generally have severely compromised healing. In comparison, pentadecapeptide BPC 157 fully improves recovery: (i) biomechanically, increased load of failure, load of failure per area and Young's modulus of elasticity; (ii) functionally, significantly higher AFI-values; (iii) microscopically, more mononuclears and less granulocytes, superior formation of fibroblasts, reticulin and collagen; (iv) macroscopically, smaller size and depth of tendon defect, and subsequently the reestablishment of full tendon integrity. Likewise, unlike TGF-beta, pentadecapeptide BPC 157, presenting with no effect on the growth of cultured cell of its own, consistently opposed 4-hydroxynonenal (HNE), a negative modulator of the growth. HNE-effect is opposed in both combinations: BPC 157+HNE (HNE growth inhibiting effect reversed into growth stimulation of cultured tendocytes) and HNE+BPC 157(abolished inhibiting activity of the aldehyde), both in the presence of serum and serum deprived conditions. In conclusion, these findings, particularly, Achilles tendon transection fully recovered in rats, peptide stability suitable delivery, usefully favor gastric pentadecapeptide BPC 157 in future Achilles tendon therapy.

Roberta K Yang James B Lowe Julia B Sobol Susan E. Mackinnon

This study explored the effects of different doses of FK506 on peripheral nerve regeneration, to determine whether neuroregeneration could be enhanced without the toxicity of systemic immunosuppression. In the first part of the study, subimmunosuppressive doses of FK506 were determined by examining skin allograft survival in a rat model. Full-thickness skin grafts (2 cm2) from Wistar rats were grafted to recipient Lewis rats. The procedure was performed for six groups (n = 6). The control group received no FK506, and the other five groups received daily doses of FK506 of 0.125, 0.25, 0.5, 1.0, or 2.0 mg/kg. Animals that received 2.0 mg/kg FK506 per day exhibited complete skin graft take, whereas all other groups demonstrated complete rejection. After determination of the immunosuppressive dose of FK506, the neuroregenerative effects of different doses of FK506 were explored by assessing nerve regeneration in 80 rats after tibial nerve transection and repair. The control group received no FK506, whereas the other four groups were given daily doses of FK506 of 0.25, 0.5, 1.0, or 2.0 mg/kg. Rats were euthanized at three time points (25, 30, and 35 days), to fully investigate the effects of different FK506 dosing regimens on neuroregeneration. Histomorphometric analyses performed on postoperative days 30 and 35 demonstrated statistically significant improvements in neuroregeneration with subimmunosuppressive FK506 doses of 0.5 and 1.0 mg/kg per day. Therefore, the study demonstrated that neuroregeneration was enhanced at low doses of FK506 that were not sufficient to prevent skin allograft rejection.

Alberto López-Avila

Ulises Coffeen J. M. Ortega-Legaspi Francisco Pellicer

The anterior cingulate cortex (ACC) plays a key role in pain processing. It has been reported that increased activity of glutamatergic projections into the ACC intensifies nociception; whereas dopaminergic projections inhibit it. The aim of this study was to evaluate the role of dopaminergic and NMDA systems of the ACC in the modulation of long-term nociception elicited by sciatic denervation in the rat. Score, onset and incidence of long-term nociception were measured by the autotomy behavior. The effects of a single microinjection into the ACC of different doses of dopamine (100 nM, 100 microM and 100 mM), a NMDA receptor antagonist (MK801 200 nM and 9.34 mM) and amantadine, a dopamine agonist and NMDA receptor antagonist (10, 100 and 1000 microM) were tested on long-term nociception. Dopamine diminished autotomy behavior in an inverse dose-dependent manner, with dopamine 100 nM as most effective concentration. MK801 and amantadine elicited a significant reduction on autotomy score. Prior injections of D1 and D2 receptor antagonists blocked the antinociceptive effects of amantadine on long-term nociceptive behavior. The present study suggests an interaction between dopaminergic and glutamatergic systems within the ACC in the genesis and maintenance of long-term nociception.

Alenka Boban Blagaic

Vladimir Blagaić Mirela Mirt

Predrag Sikiric

Serotonin syndrome commonly follows irreversible monoamine oxidase (MAO)-inhibition and subsequent serotonin (5-HT) substrate (in rats with fore paw treading, hind limbs abduction, wet dog shake, hypothermia followed by hyperthermia). A stable gastric pentadecapeptide BPC 157 with very safe profile (inflammatory bowel disease clinical phase II, PL-10, PLD-116, PL-14736, Pliva) reduced the duration of immobility to a greater extent than imipramine, and, given peripherally, has region specific influence on brain 5-HT synthesis (alpha-[14C]methyl-L-tryptophan autoradiographic measurements) in rats, different from any other serotonergic drug. Thereby, we investigate this peptide (10 microg, 10 ng, 10 pg/kg i.p.) in (i) full serotonin syndrome in rat combining pargyline (irreversible MAO-inhibition; 75 mg/kg i.p.) and subsequent L-tryptophan (5-HT precursor; 100 mg/kg i.p.; BPC 157 as a co-treatment), or (ii, iii) using pargyline or L-tryptophan given separately, as a serotonin-substrate with (ii) pargyline (BPC 157 as a 15-min posttreatment) or as a potential serotonin syndrome inductor with (iii) L-tryptophan (BPC 157 as a 15 min-pretreatment). In all experiments, gastric pentadecapeptide BPC 157 contrasts with serotonin-syndrome either (i) presentation (i.e., particularly counteracted) or (ii) initiation (i.e., neither a serotonin substrate (counteraction of pargyline), nor an inductor for serotonin syndrome (no influence on L-tryptophan challenge)). Indicatively, severe serotonin syndrome in pargyline + L-tryptophan rats is considerably inhibited even by lower pentadecapeptide BPC 157 doses regimens (particularly disturbances such as hyperthermia and wet dog shake thought to be related to stimulation of 5-HT2A receptors), while the highest pentadecapeptide dose counteracts mild disturbances present in pargyline rats (mild hypothermia, feeble hind limbs abduction). Thereby, in severe serotonin syndrome, gastric pentadecapeptide BPC 157 (alone, no behavioral or temperature effect) has a beneficial activity, which is likely, particular, and mostly related to a rather specific counteraction of 5-HT2A receptors phenomena.

M. Schäffer Nico Fuchs Julia Völker

Richard Viebahn

Tacrolimus, used in organ transplantation, inhibits cellular immune function. Little is known about the effect on dermal and colonic healing. Groups of 10 rats underwent dorsal skin incision, and polyvinyl alcohol sponges were implanted subcutaneously. Beginning at the day of wounding, rats were treated intraperitoneal with 1.0 or 2.0 mg tacrolimus/kg/day. Animals were sacrificed 10 d later to determine wound breaking strength and reparative collagen deposition. Expression of transforming growth factor (TGF)-beta, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma was studied in wounds. Groups of 8 rats underwent laparotomy and left colonic anastomosis. These rats were treated by subcutaneous injections with 2.0 or 5.0 mg tacrolimus/kg. Animals were sacrificed 5 d later to test colonic bursting pressure and reparative collagen deposition. Expression of TGF-beta, TNF-alpha, IFN-gamma, and CD4 and CD8 in the anastomosis was investigated. Tacrolimus impaired dermal healing (p < .05). This was paralleled by decreased expression of TGF-beta (stimulates healing) and increased expression of IFN-gamma and TNF-alpha (both inhibit healing) (p < .05). In contrast, tacrolimus did not inhibit healing of colonic anastomoses. No effect was seen on the expression of TGF-beta, TNF-alpha, IFN-gamma, and CD4 and CD8 in colonic anastomoses. We concluded that tacrolimus differentially effects tissue healing and expression of cellular mediators in dermal and intestinal wounds.

Tomislav Anic

Sven Seiwerth

Andrija Krivic

Predrag Sikiric

Stable gastric pentadecapeptide BPC 157 (BPC 157, as an antiulcer agent in clinical trials for inflammatory bowel disease; PLD-116, PL 14736, Pliva, no toxicity reported) alone (without carrier) ameliorates healing of tendon and bone, respectively, as well as other tissues. Thereby, we focus on Achilles tendon-to-bone healing: tendon to bone could not be healed spontaneously, but it was recovered by this peptide. After the rat's Achilles tendon was sharply transected from calcaneal bone, agents [BPC 157 (10 microg, 10 ng, 10 pg), 6alpha-methylprednisolone (1 mg), 0.9% NaCl (5 mL)] were given alone or in combination [/kg body weight (b.w.) intraperitoneally, once time daily, first 30-min after surgery, last 24 h before analysis]. Tested at days 1, 4, 7, 10, 14, and 21 after Achilles detachment, BPC 157 improves healing functionally [Achilles functional index (AFI) values substantially increased], biomechanically (load to failure, stiffness, and Young elasticity modulus significantly increased), macro/microscopically, immunohistochemistry (better organization of collagen fibers, and advanced vascular appearance, more collagen type I). 6alpha-Methylprednisolone consistently aggravates the healing, while BPC 157 substantially reduces 6alpha-methylprednisolone healing aggravation. Thus, direct tendon-to-bone healing using stabile nontoxic peptide BPC 157 without a carrier might successfully exchange the present reconstructive surgical methods.

Staresinic Mario Igor Petrovic

Tomislav Novinscak

Predrag Sikiric

We report complete transection of major muscle and the systemic peptide treatment that induces healing of quadriceps muscle promptly and then maintains the healing with functional restoration. Initially, stable gastric pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, M.W. 1419, PL-10, PLD-116, PL 14736 Pliva, Croatia; in trials for inflammatory bowel disease; wound treatment; no toxicity reported; effective alone without carrier) also superiorly accelerates the healing of transected Achilles tendon. Regularly, quadriceps muscle completely transected transversely 1.0 cm proximal to patella presents a definitive defect that cannot be compensated in rat. BPC 157 (10 microg, 10 ng, 10 pg/kg) is given intraperitoneally, once daily; the first application 30 min posttransection, the final 24 h before sacrifice. It consistently improves muscle healing throughout the whole 72-day period. Improved are: (i) biomechanic (load of failure increased); (ii) function (walking recovery and extensor postural thrust/motor function index returned toward normal healthy values); (iii) microscopy/immunochemistry [i.e., mostly muscle fibers connect muscle segments; absent gap; significant desmin positivity for ongoing regeneration of muscle; larger myofibril diameters on both sides, distal and proximal (normal healthy rat-values reached)]; (iv) macroscopic presentation (stumps connected; subsequently, atrophy markedly attenuated; finally, presentation close to normal noninjured muscle, no postsurgery leg contracture). Thus, posttransection healing-consistently improved-may suggest this peptide therapeutic application in muscle disorders.

Nune Darbinian-Sarkissian

Marta Czernik

Francesca Peruzzi

Shohreh Amini

Examination of signal transduction pathways that modulate neuronal cell differentiation and protection against apoptosis has revealed a central role for the MAPK/Erk cascade. The activation of MAPK/Erk through the TrkA NGF signaling pathway is critical for growth and survival of neuronal cells. Here, we investigate the impact of HIV-1 Tat on the NGF-signaling pathway in SK-N-MC neuroblastoma cells. Expression of Tat decreased cell growth and induced apoptosis. Our results revealed dysregulation of various steps involved in the NGF pathway including suppression of MAPK, and inhibition of the promoter activity of Egr-1, a key pleiotropic mediator of the expression of genes involved in cell growth upon expression of Tat in SK-N-MC cells. Similarly, exposure of SK-N-MC to conditioned media derived from cells expressing Tat decreased phosphorylation of MAPK and reduced the level of Egr-1 protein expression in SK-N-MC cells. Furthermore, MAPK was able to phosphorylate Puralpha, a cellular protein that plays an important role in neuronal cell function and differentiation, and this was inhibited by Tat. The ability of Puralpha to interact with a GA/GC-rich sequence positioned upstream from the transcription start site of the Egr-1 promoter provided a rationale to examine Egr-1 expression. Expression of Tat decreased NGF-induced Egr-1 levels in SK-N-MC cells and reduced binding of Puralpha to the Egr-1 promoter. All of these observations support a model where the interplay between Tat and Puralpha dysregulates the NGF pathway including the MAPK/Erk network, resulting in reduced expression and activity of Egr-1 in neuronal cells.

Alison K Snyder Ida K Fox Chris M Nichols Susan E. Mackinnon

FK-506 is used in organ transplantation because it promotes neurite outgrowth in vitro and enhances neuroregeneration in peripheral nerve injury transection models. Immunosuppressive mechanisms of FK-506 are well defined, with demonstration of decreased neuroregenerative effects with delayed administration. The purpose of this study was to describe the effects of preinjury administration of FK-506 in rats with tibial nerve transection injury. Eight inbred male Lewis rats per group in three separate groups underwent tibial nerve transection with primary repair. Group I received placebo, group II received FK-506 treatment at 1 day before surgery, and group III received FK-506 preloading 3 days before surgery. Histologic and histomorphometric results demonstrated the preload FK-506 group had superior results compared with the immediate FK-506 group. Both FK-506 groups were superior to the placebo group. The preload FK-506 demonstrated superior regeneration in mean total nerve fiber counts (p < 0.05), greater percentage neural tissue (p < 0.05), greater mean nerve fiber density (p < 0.05), and lower percentage of debris (p > 0.05). Mean nerve fiber widths were similar in the preload and immediate FK-506 groups but superior to the placebo group. These data suggest that enhancement of FK-506's neuroregenerative effect is enhanced when administered before nerve injury such as when performing elective surgery.

Vanesa Ivetic Tkalcevic

Snjezana Cuzic

Karmen Brajša

Michael Parnham

Apart from becaplermin (recombinant human platelet-derived growth factor homodimer of B chains, PDGF-BB), for the treatment of lower extremity diabetic ulcers, few agents are available for pharmacological stimulation of wound healing. We have compared the mechanism of action of the potential wound healing agent, PL 14736 (G E P P P G K P A D D A G L V), with that of PDGF-BB on granulation tissue formation following sponge implantation in the normoglycemic rat and in healing full-thickness excisional wounds in db/db genetically diabetic mice. Expression of the immediate response gene, early growth response gene-1 (egr-1) was studied in Caco-2 cells in vitro. While PDGF-BB and PL 14736 had similar selectivity for stimulation of granulation tissue in both sponge granuloma and in healing wounds in db/db mice, PL 14736 was more active in stimulating early collagen organization. It also stimulated expression of egr-1 and its repressor nerve growth factor 1-A binding protein-2 (nab2) in non-differentiated Caco-2 cells more rapidly than PDGF-BB. EGR-1 induces cytokine and growth factor generation and early extracellular matrix (collagen) formation, offering an explanation for the beneficial effects of PL 14736 on wound healing.

Study of the protective effects of pentadecapeptide BPC 157 on wounds in small type pigs

X C Xue Y J Wu M T Gao

Xue XC, Wu YJ, Gao MT. Study of the protective effects of pentadecapeptide BPC 157 on wounds in small type pigs. Chin New Drugs J 2004;12:602-4.

The development of PL 14736 for treatment of inflammatory bowel disease. IUPHAR-GI Section Symposium

M Veljaca Z Krnic K Brajsa B Mildner D Pavic-Saladojev D Seveljevic-Jaran M Kolega D Erceg Z Krznaric

Veljaca M, Krnic Z, Brajsa K, Mildner B, Pavic-Saladojev D, Seveljevic-Jaran D, Kolega M, Erceg D, Krznaric Z. The development of PL 14736 for treatment of inflammatory bowel disease. IUPHAR-GI Section Symposium 2002, Honolulu, Hawaii, O-32; 2002.

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