The influence of gastric pentadecapeptide BPC 157 on

The stable gastric pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, M.W.1419), which was promising in inflammatory bowel disease (PL-10, PLD-116, PL-14736, Pliva) trials, protects against both acute and chronic alcohol-induced lesions in stomach and liver, but also, given peripherally, affects various centrally mediated disturbances. Now, in male NMRI mice BPC 157 (10 pg intraperitoneally, 10 ng and 10 microg, intraperitoneally or intragastrically) (i) strongly opposed acute alcohol (4 g/kg intraperitoneally) intoxication (i.e., quickly produced and sustained anesthesia, hypothermia, increased ethanol blood values, 25% fatality, 90-min assessment period) given before or after ethanol, and (ii) when given after abrupt cessation of ethanol (at 0 or 3 or 7 h withdrawal time), attenuated withdrawal (assessed through 24 hours) after 20%-alcohol drinking (7.6 g/kg) through 13 days, with provocation on the 14th day.

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... Table 4. A restorative dimension of the BPC 157 therapy can react with the GABA system depending on the condition [15,[57][58][59]63,64,218]. ...

... BPC 157 therapy exhibited the counteraction of both acute and chronic alcohol effects as a highlight of the BPC 157 particular potential consistently evidenced in mice that were either acutely intoxicated or physically dependent on alcohol [63,64]. ...

... When given after abrupt cessation of chronic ethanol (at 0 or 3 h withdrawal time), it attenuated withdrawal and handling induced withdrawal seizures. [63,64] Following acute absolute alcohol intragastric administration, BPC 157 therapy attenuated/eliminated the alcohol-occlusion/occlusion-like syndrome as a whole, major vascular and multiorgan failure [56], as described above [40][41][42][43][47][48][49][50][51][52][53][54][55][56]. ...

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.

... In addition, this effect might affect general anesthesia as well [94] (i.e., BPC 157 antagonized thiopental-induced general anesthesia (parallel shift of the dose-response curve to the right) [94]). In this, illustrative of the antagonization of ethanol disorders, BPC 157 was suggested to act as an antagonist of ethanol [85,95], counteracting both acute and chronic alcohol intoxications [96,97]. Furthermore, such an antagonization might have been a particular point given to anesthetic barbiturates, such as thiopental, and the counteraction of their activities as both agonists at GABAA receptors and enhancers of receptor responses to GABA [98]. ...

... Finally, the full complexity of the brain-gut axis function might have been illustrated with the application of alcohol and the extent of the antagonization disturbances. The counteraction included behavioral disturbances in acute and chronic alcohol intoxications [96,97]. Additionally, those counteracted were hypothermia, mucosal and endothelial lesions, liver injuries, and portal hypertension [70,82,96,97,[104][105][106]. ...

... The counteraction included behavioral disturbances in acute and chronic alcohol intoxications [96,97]. Additionally, those counteracted were hypothermia, mucosal and endothelial lesions, liver injuries, and portal hypertension [70,82,96,97,[104][105][106]. Moreover, an additional illustration of both the extensive lesions and BPC 157 therapy potentials appeared in absolute alcohol intragastric administration, producing severe occlusion/occlusion-like syndrome. ...

Predrag Sikiric

Slaven Gojkovic

Ivan Krezic

Sven Seiwerth

Conceptually, a wide beneficial effect, both peripherally and centrally, might have been essential for the harmony of brain–gut and gut–brain axes’ function. Seen from the original viewpoint of the gut peptides’ significance and brain relation, the favorable stable gastric pentadecapeptide BPC 157 evidence in the brain–gut and gut–brain axes’ function might have been presented as a particular interconnected network. These were the behavioral findings (interaction with main systems, anxiolytic, anticonvulsive, antidepressant effect, counteracted catalepsy, and positive and negative schizophrenia symptoms models). Muscle healing and function recovery appeared as the therapeutic effects of BPC 157 on the various muscle disabilities of a multitude of causes, both peripheral and central. Heart failure was counteracted (including arrhythmias and thrombosis), and smooth muscle function recovered. These existed as a multimodal muscle axis impact on muscle function and healing as a function of the brain–gut axis and gut–brain axis as whole. Finally, encephalopathies, acting simultaneously in both the periphery and central nervous system, BPC 157 counteracted stomach and liver lesions and various encephalopathies in NSAIDs and insulin rats. BPC 157 therapy by rapidly activated collateral pathways counteracted the vascular and multiorgan failure concomitant to major vessel occlusion and, similar to noxious procedures, reversed initiated multicausal noxious circuit of the occlusion/occlusion-like syndrome. Severe intracranial (superior sagittal sinus) hypertension, portal and caval hypertensions, and aortal hypotension were attenuated/eliminated. Counteracted were the severe lesions in the brain, lungs, liver, kidney, and gastrointestinal tract. In particular, progressing thrombosis, both peripherally and centrally, and heart arrhythmias and infarction that would consistently occur were fully counteracted and/or almost annihilated. To conclude, we suggest further BPC 157 therapy applications.

... There is additional evidence that BPC 157 leads to a rapid rescue of vascular capacity. In an acute ethanol intoxication in mice, there is sustained anesthesia, hypothermia, increased ethanol blood values, and 25% fatality over a 90-minute assessment period (Blagaic et al., 2004). BPC 157, regardless of whether it is administered before or after ethanol intoxication, rapidly counteracts the above-mentioned negative effects (Blagaic et al., 2004). ...

... In an acute ethanol intoxication in mice, there is sustained anesthesia, hypothermia, increased ethanol blood values, and 25% fatality over a 90-minute assessment period (Blagaic et al., 2004). BPC 157, regardless of whether it is administered before or after ethanol intoxication, rapidly counteracts the above-mentioned negative effects (Blagaic et al., 2004). Furthermore, BPC 157, when given after abrupt cessation of ethanol -continuous drinking of 20% alcohol drinking for 13 days, with a provocation on day 14attenuates withdrawal (assessed over 24 hours) (Blagaic et al., 2004). ...

... BPC 157, regardless of whether it is administered before or after ethanol intoxication, rapidly counteracts the above-mentioned negative effects (Blagaic et al., 2004). Furthermore, BPC 157, when given after abrupt cessation of ethanol -continuous drinking of 20% alcohol drinking for 13 days, with a provocation on day 14attenuates withdrawal (assessed over 24 hours) (Blagaic et al., 2004). BPC 157 maintains vascular integrity to counteract alcohol leakage to tissues (Sikiric et al., 2020b), an effect that substantiates the previously emphasized evidence that BPC 157 directly protects the endothelium (Sikiric et al., 2006;, which is a hallmark in cytoprotection studies (Szabo et al., 1986). ...

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.

... 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. ...

... 11 As we reported, this special combined point that should characterize the effects of any suited cytoprotective agent in practice fulfils the corresponding range of beneficial effect of BPC 157. We noted the antagonization of the corresponding alcoholinduced [48][49][50][51][52] and NSAIDs-induced 53-57 stomach lesions, much like the counteraction of the liver and brain lesions, which were induced by alcohol [58][59][60] or NSAIDs. [53][54][55][56][57]61 To emphasize, much like the prototypic acute alcohol-stomach lesion, 48-51 the beneficial range of the BPC 157 counteracts alcohol in both acute intoxication (protracted drowsiness, increased alcohol level in blood, hypothermia) and chronic intoxication (withdrawal convulsions). ...

... [53][54][55][56][57]61 To emphasize, much like the prototypic acute alcohol-stomach lesion, 48-51 the beneficial range of the BPC 157 counteracts alcohol in both acute intoxication (protracted drowsiness, increased alcohol level in blood, hypothermia) and chronic intoxication (withdrawal convulsions). 59,60 Likewise, it counteracts consequences of the chronic abuse (drinking alcohol for 3 months) 58 such as chronic gastric lesions 51 or liver lesions with portal hypertension. 58 For NSAIDsadverse effects (i.e., gastrointestinal, liver and brain injuries), BPC 157 counteraction includes both COX-1 and COX-2 block-ers. ...

Ki-Baik Hahm

Predrag Sikiric

Alenka Boban Blagaic

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).

... Conceptually, the beneficial background on the periphery implies a corresponding beneficial central influence [22,[54][55][56][57][58][59][60][61][62][63][64][65][66]. Namely, given peripherally, BPC 157 induces the release of serotonin in particular brain nigrostriatal regions and has influence on serotonergic [58] and dopaminergic systems [57]. ...

... The observed beneficial effects were obtained within the specifically (over)stimulated or damaged dopaminergic, serotoninergic, GABAergic and opioid systems. The ample evidence on BPC 157 potential beneficial effects includes the positive influence on many central disturbances: akinesia [55,56], catalepsy [55,56,65], somatosensory disorientation [65], tremor [55,56], seizures, stereotypies (both acute and chronic) [66], hypothermia [55,56], hyperthermia, serotonin syndrome [58], acute and chronic alcohol intoxication [55,56], climbing and helpless behaviour [60], morphine-induced analgesia [63], diazepam tolerance and dependence [62], muscle weakness and function failure [54], dopamine vesicle depletion [54], amphetamine given acutely [66] and chronically [57], amphetamine tolerance [57], amphetamine supersensitivity [66], morphine and naloxone [63], picrotoxin and isoniazid convulsions [61,62], cuprizone effects, a neurotoxin mimicking multiple sclerosis brain lesions and presentation [22]. ...

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

... On the other hand, in addition to its interaction with NO system (Sikiric et al. 2014), the other findings illustrate the possibility that general anesthesia might be affected by BPC 157 administration. 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). ...

... 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. ...

... 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. Contrary to this, BPC 157 alone did not exhibit any influence either on gross behavior in normal animals, or on loss of righting reflex or any somatosensory disorientation (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. , 2002Sikiric et al. , 2011. ...

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).

... In contrast, its effects are specific in as much as ethanol interacts with discrete sites on particular proteins that are critical for protein function and for cell functioning [68]. Thus, potential therapy should deal with an inherent mechanism of action that involves multiple subcellular sites in the CNS, thereby influencing the function of most, if not all, neuronal systems at molecular, cellular and system levels [51,69]. ...

... Later, BPC 157 was proposed to be an antidote for alcohol [3]. Of note, up to now, the theoretical point of cytoprotective effect (counteraction of acute/chronic alcohol mucosal lesions) (see section (i)) is commonly not extended to a beneficial effect on acute/chronic alcohol behavioral disturbances [69]. ...

... In support for a general beneficial effect, in the same dose range, along with reducing blood levels of ethanol, the peptide also inhibits the toxic, overt behavioral and hypothermic effects of a large dose of ethanol (note, BPC 157 also counteracts hypothermic effect of reserpine [75] and serotonin-syndrome [79]). Thus, this successful effect of BPC 157 did resolve acute-chronic alcohol relation, and limited beneficial effect of standard agents on either acute or chronic alcohol effect, and a regularly opposite, worsening effect on other one [51,69]. ...

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.

... Thereby, the present study aims to focus on morphine analgesia and gastric pentadecapeptide BPC 157 (GEPPPGKPADDAGALV, M.W. 1419). It is an anti-ulcer peptide (9)(10)(11)(12), interacting with NO-system (13), and, unlike other peptides, it is particularly stable in gastric juice (14) and is used consistently without a carrier (9)(10)(11)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24), being safe in patients with the inflammatory bowel disease (coded PL-10, PLD 116, PL 14736) (21). ...

... Firstly, during its either acute or chronic administration, highly specific alphamethyl-L-tryptophan autoradiography measurements reveal that it affects the central nervous system neurotransmitters synthesis and function in specific regions. An increased serotonin synthesis in rat substantia nigra ́s (compacta and reticulate) structure (11,16,19,(22)(23)(24)(25) parallels the antidepressant effect during the Porsolt's test (17). BPC 157 reduces the duration of immobility to a greater extent than imipramine does (17) and, in addition, it counteracts the serotonin syndrome in rats (23). ...

... Interestingly, it also counteracts behavioral disturbances in amphetamine treated rats, acutely and chronically, and the haloperidol-amphetamine -climbing behavior (18,19). Thirdly, gastric pentadecapeptide BPC 157 counteracts and reverses the behavioral disturbance induced by both acute and chronic alcohol ingestion (22,24). Furthermore, it counteracts also gastric and liver lesions, induced by acute or chronic administration of alcohol (13,20). ...

Petra Turcic

Alenka Boban Blagaic

Vladimir Blagaić

Predrag Sikiric

Previously, the gastric pentadecapeptide BPC 157, (PL 14736, Pliva) has been shown to have several beneficial effects, it exert gastroprotective, anti-inflammatory actions, stimulates would healing and has therapeutic value in inflammatory bowel disease. The present study aimed to study the effect of naloxone and BPC 157 on morphine-induced antinociceptive action in hot plate test in the mouse. It was found that naloxone and BPC 157 counteracted the morphine (16 mg/kg s.c.) - analgesia. Naloxone (10 mg/kg s.c.) immediately antagonised the analgesic action and the reaction time returned to the basic values, the development of BPC 157-induced action (10 pg/kg, 10 ng/kg, 10 microg/kg i.p.) required 30 minutes. When haloperidol, a central dopamine-antagonist (1 mg/kg i.p.), enhanced morphine-analgesia, BPC 157 counteracted this enhancement and naloxone reestablished the basic values of pain reaction. BPC 157, naloxone, and haloperidol per se failed to exert analgesic action. In summary, interaction between dopamine-opioid systems was demonstrated in analgesia, BPC 157 counteracted the haloperidol-induced enhancement of the antinociceptive action of morphine, indicating that BPC acts mainly through the central dopaminergic system.

... It is likely that BPC in both the upper and lower gastrointestinal tract (Sikiric et al. 2010(Sikiric et al. , 1996(Sikiric et al. 1997a(Sikiric et al. ,b, 2001Klicek et al. 2008;Skorjanec et al. 2009;Sever et al. 2009) that is stable in human gastric juice and was proven to be effective in inflammatory bowel disease trials (PL 14736) (for review see Sikiric et al. 2010) and for various wound treatments (Skorjanec et al., 2009;Sever et al. 2009, Sikiric et al. 2003Tkalcevic et al. 2007) with no toxicity reported (for review see Sikiric et al. 2010). It may also affect many disturbances of the central nervous system (Blagaic et al. 2004;Boban Blagaic et al. 2005;Tohyama et al. 2004;Jelovac et al. 1998Jelovac et al. , 1999Sikiric et al. 1999;Tudor et al. 2010) and contain various hepatoprotective effects (Ilic et al. 2010(Ilic et al. , 2009Sikiric et al. 1993a;Prkacin et al. 2001b). In support of these studies, there is evidence that BPC 157 antagonizes stomach-liver-brain lesions induced by an overdose of insulin (Ilic et al. 2009). ...

... A well-balanced effect that affects all of the organs equally may define the same effective counteracting dosage range for all combined organs, including the stomach, intestine, liver and brain lesions in the present study. In particular, due to the gastrointestinal (Sikiric et al. 2010(Sikiric et al. , 1996(Sikiric et al. , 1997a(Sikiric et al. ,b, 2001Klicek et al. 2008;Skorjanec et al. 2009;Sever et al. 2009;Prkacin et al. 2001a), liver (Ilic et al. 2010(Ilic et al. , 2009Sikiric et al. 1993b;Prkacin et al. 2001b) and brain (Blagaic et al. 2004;Boban Blagaic et al. 2005;Tohyama et al. 2004;Jelovac et al. 1998Jelovac et al. , 1999Sikiric et al. 1999;Tudor et al. 2010) injuries as well as due to the gastric-liver-brain triad lesions after insulin overdose, the breakdown of liver glycogen occurs with profound hypoglycemia (Ilic et al. 2009). ...

... Alternatively, diclofenac might exert a more direct effect on the CNS [similar to paracetamol, which preferentially inhibits brain cyclooxygenases (Flower and Vane 1972)]. In fact, we might assume that pentadecapeptide BPC 157 has even more direct CNS beneficial effects and neuroprotective capabilities, as have been described in other studies (Blagaic et al. 2004;Boban Blagaic et al. 2005;Tohyama et al. 2004;Jelovac et al. 1998Jelovac et al. , 1999Sikiric et al. 1999;Tudor et al. 2010). In support of this hypothesis, the same BPC 157 dose range (intraperitoneally/intragastrically/locally at the site of anastomosis or directly into the tube) recently was shown to counteract paracetamol-induced hepatic encephalopathy and brain lesions (Ilic et al. 2010). ...

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.

... A solution to induce an acute hepatic toxicity and a rapidly progressing encephalopathy with severe seizures in rats may be a single paracetamol overdose (5 g/kg intraperitoneally) that excided the regimens previously used (1,2,6,11). A counteracting agent may be the stable gastric pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, MW 1419, an anti-ulcer peptide per-orally active (12)(13)(14)(15)) that may also affect many central disturbances (16)(17)(18)(19)(20)(21)(22)(23), efficient in inflammatory bowel disease trials (PL 14736) (24,25) and various wound treatment (26)(27)(28), no toxicity reported (12,13,24,25)) which showed various hepatoprotective effects (29)(30)(31). BPC 157 is stable in human gastric juice (more than 24 h), unlike rapidly degraded standard peptides such as h-EGF and h-TGF (12,13), and is recognized to be a basal protectant in saliva and gastric juice (12,13). ...

... 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 (22,34), consistent antagonization of different central disturbances (16)(17)(18)(19)(20)(21)(22)(23)34), 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) (16,20). Presenting the suggested significance of substantia nigra for controlling seizures (35), it may be important Table 8. ...

... that BPC 157/substantia nigra relation may be particularly substantiated: the increased 5-HT synthesis in substantia nigra was the most prominent one (20), counteracted 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) parkinsonian syndrome as well as the lethal outcome due to particular substantia nigra damage (17), maintained dopamine system function (BPC 157 may counteract akinesia, catalepsy induced by neuroleptics or reserpine as well as amphetamine-stereotypy behavior) (17)(18)(19). Also, BPC 157 was found to have anti-convulsive properties (16,17,21). Also very recently, with the respect of K + -ATP channels in the substantia nigra as a predisposing factor for seizure development, BPC 157 inhibits K + conductance in WT HEK293 cells (36). ...

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.

... Thereby, we focus on a so far not investigated peptide therapy for traumatic brain injury. We attempted to achieve a counteraction of these events by the stable gastric pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, MW 1419, a small anti-ulcer peptide protecting endothelium [3][4][5][6][7][8][9][10][11][12][13][14]16,17] that may also affect many central disturbances [16][17][18][19][20][21][22] and NO-system [4,13,15,19] and act as free radical scavenger [36], efficient in inflammatory bowel disease trials (PL 14736) [23,24] and various wound treatment [25][26][27][28][29][30][31][32][33][34][35], no toxicity reported [23,24]). Interestingly, it was an effective therapy of muscle crush injury in rats [34,35]. ...

... Medication, without carrier or peptidase inhibitor, includes pentadecapeptide BPC 157 (a partial sequence of human gastric juice protein BPC, freely soluble in water at pH 7.0 and in saline; a peptide with 99% (HPLC) purity (1-des-Gly peptide as impurity), manufactured by Diagen, Ljubljana, Slovenia, GEPPPGKPADDAGLV, M.W. 1419 [3][4][5][6][7][8][9][11][12][13][14][15][16][17][18][19][20][21][22]25,[28][29][30][31][32][33][34][35][36]38,40], dissolved in saline (10.0 μg, 10.0 ng, 100.0 pg, 10.0 pg and 1.0 pg/kg b.w.)), or saline (5.0 ml/kg), applied intraperitoneally. ...

... Medication was given intraperitoneally at 30 min before injury induction. Pentadecapeptide BPC 157 was applied using previously effective regimens (10.0 μg, 10.0 ng/kg b.w.) [3][4][5][6][7][8][9][11][12][13][14][15][16][17][18][19][20][21][22]25,[28][29][30][31][32][33][34][35][36]38,40]. The mice from the control group received at the time of medication an equivolume of saline (5 ml/kg i.p.). ...

Mario Tudor

Ivan Jandric

Anton Marović

Predrag Sikiric

Gastric pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, an anti-ulcer peptide, efficient in inflammatory bowel disease trials (PL 14736), no toxicity reported, improved muscle crush injury. After an induced traumatic brain injury (TBI) in mice by a falling weight, BPC 157 regimens (10.0microg, 10.0ng/kgi.p.) demonstrated a marked attenuation of damage with an improved early outcome and a minimal postponed mortality throughout a 24h post-injury period. Ultimately, the traumatic lesions (subarachnoidal and intraventricular haemorrhage, brain laceration, haemorrhagic laceration) were less intense and consecutive brain edema had considerably improved. Given prophylactically (30 min before TBI) the improved conscious/unconscious/death ratio in TBI-mice was after force impulses of 0.068 Ns, 0.093 Ns, 0.113 Ns, 0.130 Ns, 0.145 Ns, and 0.159 Ns. Counteraction (with a reduction of unconsciousness, lower mortality) with both microg- and ng-regimens included the force impulses of 0.068-0.145 Ns. A higher regimen presented effectiveness also against the maximal force impulse (0.159 Ns). Furthermore, BPC 157 application immediately prior to injury was beneficial in mice subjected to force impulses of 0.093 Ns-TBI. For a more severe force impulse (0.130 Ns, 0.145 Ns, or 0159 Ns), the time-relation to improve the conscious/unconscious/death ratio was: 5 min (0.130 Ns-TBI), 20 min (0.145 Ns-TBI) or 30 min (0.159 Ns-TBI).

... A few years later, in 2004 and 2006, other researchers [9,76] supplemented the previously published study with new results that additionally pointed to the positive effect of the peptide in reducing the physiological and behavioral negative effects triggered by acute or chronic alcohol consumption. For example, preclinical in vivo studies performed by Boban-Blagic et al. [76] showed that the peptide reduced the severity of ethanol withdrawal after chronic treatment (13 days), which manifested itself in the form of tremors and tonic-clonic seizures. ...

Michalina Józwiak Marta Bauer Wojciech Kamysz

Patrycja Kleczkowska

BPC 157, known as the “Body Protection Compound”, is a pentadecapeptide isolated from human gastric juice that demonstrated its pleiotropic beneficial effects in various preclinical models mimicking medical conditions, such as tissue injury, inflammatory bowel disease, or even CNS disorders. Unlike many other drugs, BPC 157 has a desirable safety profile, since only a few side effects have been reported following its administration. Nevertheless, this compound was temporarily banned by the World Anti-Doping Agency (WADA) in 2022 (it is not currently listed as banned by the WADA). However, it has not been approved for use in standard medicine by the FDA and other global regulatory authorities due to the absence of sufficient and comprehensive clinical studies confirming its health benefits in humans. In this review, we summarize information on the biological activities of BPC 157, with particular reference to its mechanism of action and probable toxicity. This generated the attention of experts, as BPC 157 has been offered for sale on many websites. We also present recent interest in BPC 157 as reflected in a number of patent applications and granted patents.

... Given the muscle weakness that is part of the prime disturbance, vascular failure [66,[71][72][73][74][75][76][77][78][79][80][81][82], stroke [20], traumatic brain injury [21], spinal cord compression [28,29], vessel occlusion and similar noxious procedures [66,[71][72][73][74][75][76][77][78][79][80][81][82] were all specifically highlighted in the literature. Furthermore, the literature also focused on the succinylcholine-induced neuromuscular junction blockade [102], local anesthesia [103,104] (i.e., via lidocaine intraplantar application and axillary and spinal (L4-L5) intrathecal block [103]), electrolytes disturbances [19,55,80,105,106], neuroleptics dopamine blockade [26,51,54,55], NO-system blockade [26], alcohol intoxication [22], serotonin syndrome [25], particular neurotoxins (inducing Parkinson-like disturbances in mice [30] or multiple sclerosis-like disturbances in rats [31]), and tumor cachexia [10]. These intriguing relations might also include, besides the striated muscle, the smooth muscle (i.e., various sphincter functions) [73,91,[107][108][109][110][111][112][113][114][115][116][117][118][119][120][121], and the heart muscle [6,54,72,74,[76][77][78][79][80][81][82]105,106,[121][122][123]. ...

... Similarly counteracted were the consequences of electrolytes disturbances [19,55,80,105,106], neuroleptics dopamine blockade [26,51,54,55], NO system blockade [26], particular neurotoxins (inducing Parkinson's-like disturbances in mice [30] or multiple sclerosis-like disturbances in rats [31]). Furthermore, alcohol intoxication [22], and serotonin-syndrome [25] were counteracted. Finally, tumor-cachexia was counteracted [10]. ...

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 is also a strong, dose-dependent association between the number of alcoholic drinks consumed per day and acute lung injury and ARDS [23]. In addition to its previously described effects on vessel recruitment [11][12][13][14][15][16][17][36][37][38][39] BPC 157 counteracts chronic alcohol consumption-induced stomach lesions, liver failure and portal hypertension [74,75], acute alcohol (4 g/kg intraperitoneally) intoxication, and chronic (withdrawal) alcohol intoxication [73,76]. When administered before or after ethanol, BPC 157 acts as an alcohol antagonist and provides extended cytoprotective effects against the anesthesia, hypothermia, increased ethanol blood values and fatality [76,77], opposes thiopental anesthesia [78], and counteracts various encephalopathies [79][80][81][82][83][84] in rats. ...

... In addition to its previously described effects on vessel recruitment [11][12][13][14][15][16][17][36][37][38][39] BPC 157 counteracts chronic alcohol consumption-induced stomach lesions, liver failure and portal hypertension [74,75], acute alcohol (4 g/kg intraperitoneally) intoxication, and chronic (withdrawal) alcohol intoxication [73,76]. When administered before or after ethanol, BPC 157 acts as an alcohol antagonist and provides extended cytoprotective effects against the anesthesia, hypothermia, increased ethanol blood values and fatality [76,77], opposes thiopental anesthesia [78], and counteracts various encephalopathies [79][80][81][82][83][84] in rats. Similarly to its counteraction of encephalopathies [79][80][81][82][83][84], BPC 157 likely counteracts multiple pathologies in the gastrointestinal tract and liver [79][80][81][82][83][84]. ...

Slaven Gojkovic

Hrvoje Vranes

Ivan Krezic

Predrag Sikiric

We redefined Robert’s prototypical cytoprotection model, namely the intragastric administration of 96% alcohol in order to generate a general peripheral and central syndrome similar to that which occurs when major central or peripheral veins are occluded in animal models. With this redefinition, we used Robert’s model to examine the cytoprotective effects of the stable gastric pentadecapeptide BPC 157. The intragastric administration of alcohol induced gastric lesions, intracranial (superior sagittal sinus) hypertension, severe brain swelling and lesions, portal and vena caval hypertension, aortal hypotension, severe thrombosis, inferior vena cava and superior mesenteric vein congestion, azygos vein failure (as a failed collateral pathway), electrocardiogram disturbances, and heart, lung, liver and kidney lesions. The use of BPC 157 therapy (10 μg/kg or 10 ng/kg given intraperitoneally 1 min after alcohol) counteracted these deficits rapidly. Specifically, BPC 157 reversed brain swelling and superior mesenteric vein and inferior vena caval congestion, and helped the azygos vein to recover, which improved the collateral blood flow pathway. Microscopically, BPC 157 counteracted brain (i.e., intracerebral hemorrhage with degenerative changes of cerebral and cerebellar neurons), heart (acute subendocardial infarct), lung (parenchymal hemorrhage), liver (congestion), kidney (congestion) and gastrointestinal (epithelium loss, hemorrhagic gastritis) lesions. In addition, this may have taken place along with the activation of specific molecular pathways. In conclusion, these findings clarify and extend the theory of cytoprotection, offer an approach to its practical application, and establish BPC 157 as a prospective cytoprotective treatment.

... Furthermore, strongly antagonized intragastric ethanol-gastric lesions [44,[78][79][80][81][82] combined with mentioned long lasting no degradation in human gastric juice (as well as isolation from human gastric juice) [1] may provide convincing evidence for constantly maintained mucosa [1]. Likewise, the same alcohol essential background, ethanol lesions in stomach and the other damaging effects, the more likely is the demonstration of the full counteraction of alcohol intoxication, acute (i.e., increased alcohol blood values, sustained anesthesia and hypothermia, no righting reflex and reaction to external stimuli result in 25% mortality) as well as chronic (i.e., withdrawal prominent seizures) [1,83,84]. Thus, had it been assailed by the alcohol, BPC 157 local to systemic effect was about to determine an active gut-brain axis or brain-gut axis functioning (a point especially reviewed elsewhere [8]). And accordingly, in alcohol chronically drinking rats BPC 157 antagonizes chronic gastric lesions [81], prevents as well as reverses liver lesions and portal hypertension [86], and lung lesions aggravated by alcohol [82,85]. ...

... In support, favoring such an effect on endothelium, advancing its local to systemic effect, BPC 157 largely interacts with NO-system, as already reviewed [5,6]. Of note, the evidence consistently obtained in many different models and species highlights these special BPC 157-NO-system relationships [5,6,26,68,69,74,75,80,84,93,95,113,[117][118][119][124][125][126][127][128][129]. In particular, BPC 157 induces a release of NO (just in the rat stomach tissue using original Whittle's procedure an effect that could be alike in other tissue as well) resistant to L-NAME, and competing with NO-release induced by L-arginine [80]. ...

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.

... Thus, as a particular point of the BPC 157 activities (i.e., BPC 157 counteracted lidocaine arrhythmias, local anesthetic effect, and convulsions [72]), it might be that BPC 157 activities might approach and modulate the long-ago suggested antiarrhythmic agents potential throughout myocardial ischemia-arrhythmia-local anesthetic-anti-convulsion potential (for review, see, i.e., [182]). Illustratively, in addition to the lidocaine-induced convulsion antagonization, BPC 157 might counteract standard convulsants (i.e., picrotoxine, strychnine, bicuculline, metrazole)-induced seizures [169], as well as the insulin- [96], paracetamol [91], alcohol withdrawal [196] and serotonin syndrome- [197] induced convulsion. In addition to the lidocaine-local anesthetic effect [71], BPC 157 also counteracted tetracaine and the oxybuprocaine effect on corneal anesthesia [198] and bupivacaine severe arrhythmias [70]. ...

Mario Udovicic Ivan Barisic

Predrag Sikiric

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.

... Indicatively, there is quite strong evidence for the BPC 157 maintaining of the prostaglandins-system (34), which function is essential in the cytoprotection concept (4)(5)(6)(7)(8) and in the BPC 157 cytoprotective effectiveness (35). BPC 157 largely antagonizes all alcohol-induced lesions (19,29,(36)(37)(38)(39)(40)(41)(42) and counteracts nonsteroidal anti-inflammatory drugs (NSAIDs)-induced adverse effects (43)(44)(45)(46)(47)(48)(49)(50)(51), including leaky gut (51). The therapy effect includes nonspecific NSAIDs (43)(44)(45)(46)(47)(48)(49)51) and specific NSAID (50), in particular, curing stomach lesions that regularly were perforated or about to perforate (34). ...

Zdenko Bilic

Luka Kalogjera

Slaven Gojkovic

Predrag Sikiric

Surgically perforated stomach (since direct injury in rats until persisting defect and huge adhesions (day 1, day 7)) fairly represent an unresolved cytoprotection issue, and thereby, we focused resolving of the immediate triad, particular vascular failure (vessels 'disappear'/empty), prolonged bleeding, debilitated defect large widening. Agents (mg/kg) or saline (controls) were given at 1 min post-injury as an abdominal bath (10 ml/rat throughout 2 min). Within 1 - 15 min post-injury period, with cytoprotective BPC 157 (0.01 μg), the rapidly restored vessels 'run' (vessels filled/reappeared) toward the perforated defect, and there is less bleeding, and defect contraction; advanced perforated lesion healing (day 1) to complete healing (day 7), and less adhesions. With pantoprazole (10 mg), early (vessels (worsening), bleeding (prolongation), defect (attenuated widening)) effect means eventual lesions and adhesions severity as in controls. Ranitidine (10 mg) early effect (vessels (improvement), bleeding (less bleeding), defect (eliminated widening, defect not changed)) means final lesions attenuation, but not complete healing, less adhesions. L-NAME (5 mg) early (vessels worsening, less bleeding, attenuated defect widening) and final (lesions aggravation, more adhesions) effect, versus L-arginine (100 mg) early (vessels improvement, more bleeding, attenuated defect widening) and final (lesions attenuation, less adhesions) effect, combined few simultaneously occurring nitric oxide (NO)-system distinct processes. Finally, in the stomach tissue surrounding defect, increased malondialdehyde (MDA)- and decreased NO-values, BPC 157 reversed to the normal healthy values, and mRNA expression studies (Cox2, VEGFa, Nos1, Nos 2, Nos3, Nkap (NF-kappa-B-activating protein gene)), done at that very early post-perforation-time, indicate a way how BPC 157 may act beneficially in the perforated stomach lesion throughout NO- and prostaglandinds-system.

... These functions are important for cerebral microvascular tone regulation, BBB integrity, and procoagulant stimulation [18,88]. Further, BPC 157 has shown to modulate neurotransmitter systems such as dopaminergic [82], serotonergic [94], GABAergic [43], and opioid systems [10]. Reestablishing homeostasis in these neurotransmitter systems allows better resilience for COVID-19 patients. ...

Sarah Deek

The emergence of coronavirus disease (COVID-19) in China at the end of 2019 has caused a large global outbreak. COVID-19 is largely seen as a thrombotic and vascular disease targeting endothelial cells (ECs) throughout the body that can provoke the breakdown of central vascular functions. This explains the complications and multi-organ failure seen in COVID-19 patients including acute respiratory distress syndrome, heart failure, liver damage, and neurological damage. Acknowledging the comorbidities and potential organ injuries throughout the course of COVID-19 is therefore crucial in the clinical management of patients. Here we discuss BPC 157, based primarily on animal model data, as a novel agent that can improve the clinical management of COVID-19 via its innate endothelial protective and cytoprotective properties which leads to improved vascular integrity and immune response, reduced proinflammatory profile, and reduced critical levels of the disease. BPC 157 is a peptide that has demonstrated anti-inflammatory, cytoprotective, and endothelium-protecting effects in different organ systems in various species. BPC 157-activated endothelial nitric oxide synthase (eNOS) is associated with nitric oxide (NO) release, tissue repair and angiomodulatory properties as reported in previous studies. As a result, discussion of its use as a potential prophylactic and complementary treatment is critical. All examined treatments, although potentiality effective against COVID-19, need either appropriate drug development or clinical trial to be suitable for clinical use.

Sarah Deek

Populations in areas with higher levels of air pollution both indoors and outdoors show increased mortality rates when infected with coronavirus disease 2019 (COVID-19). The association between air quality and COVID-19 is commonly attributed to the risk of transmission. Although controlled transmission is crucial, further investigation into air quality traits that contribute to the lethality of COVID-19 in infected persons enables risk stratification and optimization of the allocation of resources. There is a need for a valid basis for the proactive identification of indicators of COVID-19 severity in air quality that allow for the implementation of systematic environmental improvements aimed at preventing COVID-19 mortality. In this paper, chronic exposure to fine particulate matter (PM) is identified as a source of disrupted activation of the hypothalamic–pituitary–adrenal (HPA) axis; it is therefore, a contributable variable to COVID-19 mortality.

... Likewise, there are various agents potentiating lidocaine-induced convulsions (such as L-arginine [56], reserpine, methysergide [57], reduction in PaCO2 and/or increase in PaO2 [67], 4L-DOPA, methamphetamine, desipramine [61], and ketamine) [65]. ereby, it may be important that the BPC 157 anticonvulsant potential counteracts variously induced seizures in rats and mice [27,37,39,69]. Also, BPC 157 interacts with several systems [1][2][3][4][5][6][7][8][9][10][11][12][13] implicated in lidocaineinduced convulsions [56][57][58][59][60][61] and may therefore modulate their activities. ...

Marin Lozić

Vasilije Stambolija

Ivan Krezic

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 also acts as a free radical scavenger, and normalizes NO-and MDAlevels in tissues, in ischemia and reperfusion [38,39,59,70,[86][87][88] with the recently demonstrated recruitment of blood vessels to bypass vascular occlusion [38,39,59,87] in rats with the ischemic/reperfusion colitis [87], duodenal congestion [39] and cecum perforation lesions [38] or infrarenal occlusion of inferior caval vein [59]. In a more extensive view on the fistulas healing [4][5][6][7][8][9][10][11][12][13][14][15][16][17], further studies are required to postulate the significance of the beneficial effect of BPC 157 on other lesions, obtained also with the same doses range used in fistulas studies, i.e., chronic heart failure [89] or various arrhythmias (72,(90)(91)(92)(93)(94), bile duct ligationinduced liver cirrhosis [88], or CNS-disturbances [9,91,[95][96][97][98][99]. ...

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.

... Also, important for the BPC 157's anti-ulcer effect, the counteraction of gastrointestinal, i.e., stomach ulcer, was along with counteraction of other presented disturbances, thus, stomach ulcer may be a part of a larger syndrome, and counteraction of stomach ulcer a part of its larger therapeutic effect [1][2][3][4][5][6]. Ilustrative may be the beneficial effect on alcohol (i.e., BPC 157 counteracts alcohol acute [33,91] and chronic gastric lesions [92], liver lesion and portal hypertension [93], and aspiration [94,95] and behavioral disturbances after acute alcohol intoxication and seizures withdrawal after chronic alcohol intoxication) [35,96]), NSAIDs (i.e., BPC 157 counteracts NSAIDs-gastric, intestinal, liver and brain lesions and bleeding disturbances) [97][98][99][100]. Also, we demonstrated that BPC 157 counteracts the development of alloxan-induced gastric ulcer [101], increases the healing of the skin wound in diabetic animals given topically [102], counteracts hypertension induced by fructose intake and resistance to insulin [1]. ...

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.

... BPC 157 exhibits a consistent counteracting effect on alcohol disturbances [for review see, i.e., (Sikiric et al. 2010(Sikiric et al. , 2011(Sikiric et al. , 2012]. Specifically, beneficial effects include treatment of acute and chronic alcohol stomach and liver lesions, including portal hypertension, and behavioral disturbances induced with either acute or chronic alcohol intoxication (Blagaic et al. 2004;Boban-Blagaic et al. 2006;Prkacin et al. 2001aPrkacin et al. , 2001bSikiric et al. 1997Sikiric et al. , 1999aSikiric et al. , 2006. That effect seems to be NO-dependent as well [for review see, i.e., (Sikiric et al. 2014)]. ...

Kresimir Luetic

Mario Sucic

Josipa Vlainić

Predrag Sikiric

We revealed a new point with cyclophosphamide (150 mg/kg/day intraperitoneally for 7 days): we counteracted both rat stomach and duodenal ulcers and increased NO- and MDA-levels in these tissues. As a NO-system effect, BPC 157 therapy (10 μg/kg, 10 ng/kg, intraperitoneally once a day or in drinking water, till the sacrifice) attenuated the increased NO- and MDA-levels and nullified, in rats, severe cyclophosphamide-ulcers and even stronger stomach and duodenal lesions after cyclophosphamide + l-NAME (5 mg/kg intraperitoneally once a day). l-arginine (100 mg/kg intraperitoneally once a day not effective alone) led l-NAME-values only to the control values (cyclophosphamide + l-NAME + l-arginine-rats). Briefly, rats were sacrificed at 24 h after last administration on days 1, 2, 3, or 7, and assessment included sum of longest lesions diameters (mm) in the stomach and duodenum, oxidative stress by quantifying thiobarbituric acid reactivity as malondialdehyde equivalents (MDA), NO in stomach and duodenal tissue samples using the Griess reaction. All these parameters were highly exaggerated in rats who underwent cyclophosphamide treatment. We identified high MDA-tissue values, high NO-tissue values, ulcerogenic and beneficial potential in cyclophosphamide-l-NAME-l-arginine-BPC 157 relationships. This suggests that in cyclophosphamide damaged rats, NO excessive release generated by the inducible isozyme, damages the vascular wall and other tissue cells, especially in combination with reactive oxygen intermediates, while failing endothelial production and resulting in further aggravation by l-NAME which was inhibited by l-arginine. Finally, BPC 157, due to its special relations with NO-system, may both lessen increased MDA- and NO-tissues values and counteract effects of both cyclophosphamide and l-NAME on stomach and duodenal lesions.

... Thus, paracetamol-, diclofenac-and ibuprofen-encephalopathy, all counteracted in an equally consistent way [5][6][7], should certainly be a worthy hallmark. Besides antagonizing hyperammonemia, i.e., in paracetamol encephalopathy, BPC 157 interacts with several neurotransmitters in the central nervous system (i.e., dopamine [27][28][29][30]39,76,77], serotonin [38], opioid [78], GABA [79,80]); specifically, when given peripherally it affects serotonin synthesis in particular brain areas, especially increasing serotonin release in the substantia nigra [38] that may be particularly beneficial in the prevention and treatment of hepatic encephalopathy [81]. ...

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.

... BPC 157 may protect liver against different noxious events, mild (fatty liver) till severe (necrosis), providing a wide range of protection against ischemia, bile duct ligation, formation of free radicals (CCl4, paracetamol, diclofenac), severe intestinal lesions and increased toxins formation (diclofenac), and severe hepatic encephalopathy (paracetamol, diclofenac, ibuprofen). Effects are also observed in continuous alcohol drinking, portal hypertension, insulin over-dose-hypoglycemia and glycogen deprivation [17,39,40,42,43,[57][58][59][60]. Generally, BPC 157, g-ng-regimens given alone intraperitoneally, intragastrically, or per-orally in drinking water, dose-regimens and application methods which have been successfully used before in other experiments, in the healing process convert rapidly from a failure to a success permitting liver function in either condition (for review see, [i.e., 1]). ...

Predrag Sikiric

Sven Seiwerth Rudolf Rucman Bozidar Sebecic

Stable gastric pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, M.W. 1419) may be the new drug stable in human gastric juice, effective both in the upper and lower GI tract, and free of side effects. BPC 157, in addition to an antiulcer effect efficient in therapy of inflammatory bowel disease (IBD) (PL 14736) so far only tested in clinical phase II, has a very safe profile, and exhibited a particular wound healing effect. It also has shown to interact with the NO-system, providing endothelium protection and angiogenic effect, even in severely impaired conditions (i.e., it stimulated expression of early growth response 1 gene responsible for cytokine and growth factor generation and early extracellular matrix (collagen) formation (but also its repressor nerve growth factor 1-A binding protein-2)), important to counteract severe complications of advanced and poorly controlled IBD. Hopefully, the lessons from animal studies, particularly advanced intestinal anastomosis healing, reversed short bowel syndrome and fistula healing indicate BPC 157's high significance in further IBD therapy. Also, this supportive evidence (i.e., no toxic effect, limit test negative, LD1 not achieved, no side effect in trials) may counteract the problems commonly exercised in the use of peptidergic agents, particularly those used on a long-term basis.

... 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). Also, BPC 157 was found to have anti-convulsive properties (37,41). Also very recently, with the respect of KATP channels in the substantia nigra as a predisposing factor for seizure development, BPC 157 inhibits K + conductance in WT HEK293 cells (42). ...

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.

... For instance, unlike standard agents implicated in alcohol acute/chronic intoxication or lesions induction, BPC 157's evidence seems to be more complete. BPC 157 may oppose the acute alcohol intoxication (i.e., BPC 157 antagonized anesthesia and hypothermia, reduced alcohol serum concentration) as well as alcohol withdrawal after chronic alcohol drinking [85,86], both acute and chronic gastric and liver lesions (including portal hypertension) [11,13,19,25,26,46]. Thereby, it may be a prototype of antagonists of alcohol. ...

Rudolf Rucman Bozidar Sebecic

Predrag Sikiric

Sven Seiwerth

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.

... BPC 157 has been proven in clinical trials to be both safe in inflammatory bowel disease (PL-10, PLD-116, PL 14736 Pliva, Croatia) [11,12] and wound healing [13][14][15][16][17][18][19], and stable in human gastric juice [20], with no toxicity being reported [11,12]). In relation to cytoprotection and ulcerogens that may break stomach mucosa (i.e.,alcohol, non-steroidal anti-inflammatory drugs (NSADs) [21][22][23]) and mucosal cytoprotective ability that may be afforded BPC 157 exhibited a particular beneficial effect on alcohol-lesions (i.e., induced acutely and chronically) [1,5,6,8,[24][25][26] and non-steroidal anti-inflammatory drugs-lesions (while interestingly BPC 157 may both prevent and reverse adjuvant arthritis) [27], the effects likely related to interaction with NOsystem [i.e., 6,26]. To review the importance of BPC 157, this review focused on Robert's cytoprotection concept described in rat stomach [21][22][23], reviewing our evidence that may resolve whether the cytoprotection and adaptive cytoprotection is an uniform phenomenon or not; whether the phenomenon or phenomena are endogenous or not, depending on nature of the irritants (mild or strong); whether this may contribute to stomach mucosa defense either when menaced by various ulcerogens or afforded by various anti-ulcer agents; whether these phenomena are uniform in whole gastrointestinal tract or not; whether they are interrelated or not. ...

Sven Seiwerth

Luka Brcic

Danijela Kolenc

Predrag Sikiric

The significance of cytoprotection and adaptive cytoprotection and the peptides importance remained to be not completely determined. 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, and stable in human gastric juice, with no toxicity being reported. It has a prominent effect on alcohol- lesions (i.e., induced acutely and chronically) and non-steroidal anti-inflammatory drugs-lesions (while interestingly BPC 157 may both prevent and reverse adjuvant arthritis). To review the importance of BPC 157, this review focused on Robert's cytoprotection concept described in rat stomach, reviewing our evidence that may resolve whether the cytoprotection and adaptive cytoprotection is an uniform phenomenon or not; whether the phenomenon or phenomena are endogenous or not, depending on nature of the irritants (mild or strong); whether this may contribute to stomach mucosa defense either when threaten by various ulcerogens or afforded by various antiulcer agents; whether these phenomena are uniform in whole gastrointestinal tract or not; whether they are interrelated or not. Finally, the importance of the cytoprotection phenomena and cytoprotection activity for skin wound healing, and wound healing in general was challenged. Thereby, this review focused on BPC 157 role in cytoprotection and adaptative cytoprotection suggesting that it may be the essential endogenous mediator able to mediate both cytoprotective and adaptive cytoprotective response in stomach and the whole gastrointestinal tract with significant importance in wound healing as well.

Danijel Matek Irena Matek Mladen Japjec Mario Staresinic

As a novel theoretical and practical advantage, preclinical to clinical evidence, this systematic review of PRP, growth factors, and stable gastric pentadecapeptide BPC 157 efficacy in complex musculoskeletal and junctional injuries emphasizes the cytoprotection concept, healing to restore tissue integrity. Notably, the concept holds tendon, ligament, and muscle healing, in particular. Then, it holds their healing together as interconnected lesions. Consequently, this review presents the possibilities for cytoprotective therapies suited for tendon/ligament/muscle and recovery of osteotendinous, myotendinous, and the muscle-to-bone junction. The estimated key was the success of injury recovery amid each agent’s direct exogenous administration, alone or with a carrier, locally or systemically, without reliance on complex scaffolds, carriers, or tissue-engineering constructs. As reviewed, while with commonly acknowledged physiological significance, and acting throughout cytoprotection principles, growth factors (PDGF, TGF-β1, IGF-1, FGF, VEGF, BMPs) delivered locally with various carriers improve tendon, ligament, and muscle healing; however, some (PDGF, TGF-β1, IGF-1) may fail in muscle lesions, and all show limited or no efficacy in junctional healing. Contrarily, proposed as a cytoprotection mediator, BPC 157 acts alone with a full cytoprotection range, given systemically or locally. Moreover, without any carrier, BPC 157 acts alone, combining beneficial effects on tendon, ligament, and muscle injuries with osteotendinous, myotendinous, and muscle-to-bone healing. In rat studies, across systemic (intraperitoneal, intragastric, or drinking water) and local (cream) administration, BPC 157 consistently demonstrated efficacy, indicating considerable translational potential. Further clinical studies will strengthen cytoprotective therapy and, particularly, BPC 157 in complex musculoskeletal and junctional injuries.

Predrag Sikiric Ivan Barisic

Mario Udovicic

Anita Skrtic

This review examines and hypothesizes cytoprotection as a conceptual therapeutic criterion for antiarrhythmic drugs, referring to the possibility of suppressing arrhythmias while avoiding adverse electrophysiological or systemic effects. Toward a theoretically complete cytoprotective profile—preserving benefits and eliminating toxicity—the criterion was the degree of counteraction of arrhythmias (i.e., bradycardia, tachycardia, atrioventricular (AV) block, ventricular tachycardia (VT), ST-segment changes, prolonged P, PR, QRS, and QT/QTc intervals, and repolarization). Conventional and new antiarrhythmics share class I–IV ≈ partial cytoprotection/narrow range; late INa inhibitors, IKs enhancers, RyR2 stabilizers, gap junction modulators, and atrial-selective antiarrhythmics ≈ partial cytoprotection/more extended range. Still predominantly in preclinical models, stable gastric pentadecapeptide BPC 157, in the clinic, has not demonstrated adverse effects in available human trials (non-cardiac) to date. As a prominent cytoprotection mediator (LD1 not achieved in toxicology studies), it demonstrates well-matched cytoprotective–antiarrhythmic effects, BPC 157 ≈ full cytoprotection/wide-range homeostasis. In vivo, this was across models of hypo-/hyperkalemia, hypermagnesemia, ischemia–reperfusion, myocardial infarction, drug-induced arrhythmias (including local anesthetics), and vascular occlusion. BPC 157 restores sinus rhythm, normalizes P/QRS/QT intervals, prevents AV block, suppresses VT, attenuates ST-segment changes, and stabilizes heart rate, even when insults are advanced. In vitro, HEK293 studies confirm direct membrane-stabilizing actions: BPC 157 prevents hypokalemia-induced hyperpolarization, reduces hyperkalemia- and hypermagnesemia-induced depolarization, and mitigates local anesthetic-induced Na+/Ca2+ dysregulation, reflecting bidirectional homeostatic modulation of membrane potential. Thus, to confirm the hypothesis, these BPC 157 conditional, not constitutive effects, in rodent models or in vitro systems (HEK293 cells), mandate expansion of now limited clinical data and mechanisms in human investigated as a translational cytoprotective strategy for complex arrhythmias.

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.

Aleksey Shchulkin Yu. V. Abalenikhina Pavel Y. Mylnikov

The effectiveness of ethylmethylhydroxypyridine succinate (EMHPS) in acute alcohol intoxication was tested in a study on SPF male outbred ICR mice. Ethanol (concentration 40%) was administered to animals once intraperitoneally at a dose of 4 g/kg. Control animals were injected with saline in an equivalent volume. In 15 min after the administration of alcohol, the animals were injected intravenously or intramuscularly with EMHPS at a dose of 50 or 100 mg/kg or with saline via the same route in an equivalent volume. Animal behavior was tested 3 and 24 h later after administration of the substances. After 3 and 24 h, mice in the pathological control groups developed semiptosis, the gait and the turning over reflex were impaired, the strength of the hind limbs decreased and the distance between the hind limbs increased when landing; in the open-field test, the latency of the first movement increased, and the number of rearing postures decreased. Intravenous and intramuscular administration of EMHPS in doses of 50 and 100 mg/kg had a pronounced antitoxic and neuroprotective effect in acute alcohol intoxication: all studied parameters did not differ significantly from the control.

Zeljka Belosic Halle

Josipa Vlainić Domagoj Drmic

Predrag Sikiric

The ulcerogenic potential of dopamine antagonists and L-NAME in rats provides unresolved issues of anti-emetic neuroleptic application in both patients and experimental studies. Therefore, in a 1-week study, we examined the pressures within the lower oesophageal and the pyloric sphincters in rats [assessed manometrically (cm H2O)] after dopamine neuroleptics/prokinetics, L-NAME, L-arginine and stable gastric pentadecapeptide BPC 157 were administered alone and/or in combination. Medication (/kg) was given once daily intraperitoneally throughout the 7 days, with the last dose at 24 h before pressure assessment. Given as individual agents to healthy rats, all dopamine antagonists (central [haloperidol (6.25 mg, 16 mg, 25 mg), fluphenazine (5 mg), levomepromazine (50 mg), chlorpromazine (10 mg), quetiapine (10 mg), olanzapine (5 mg), clozapine (100 mg), sulpiride (160 mg), metoclopramide (25 mg)) and peripheral(domperidone (10 mg)], L-NAME (5 mg) and L-arginine (100 mg) decreased the pressure within both sphincters. As a common effect, this decreased pressure was rescued, dose-dependently, by BPC 157 (10 μg, 10 ng) (also note that L-arginine and L-NAME given together antagonized each other's responses). With haloperidol, L-NAME worsened both the lower oesophageal and the pyloric sphincter pressure, while L-arginine ameliorated lower oesophageal sphincter but not pyloric sphincter pressure, and antagonized L-NAME effect. With domperidone, L-arginine originally had no effect, while L-NAME worsened pyloric sphincter pressure. This effect was opposed by L-arginine. All these effects were further reversed towards a stronger beneficial effect, close to normal pressure values, by the addition of BPC 157. In addition, NO level was determined in plasma, sphincters and brain tissue. Thiobarbituric acid reactive substances (TBARS) were also assessed. Haloperidol increased NO levels (in both sphincters, the plasma and brain), consistently producing increased TBARS levels in the plasma, sphincters and brain tissues. These effects were all counteracted by BPC 157 administration. In conclusion, we revealed that BPC 157 counteracts the anti-emetic neuroleptic class side effect of decreased pressure in sphincters and the dopamine/NO-system/BPC 157 relationship.

A.B. Batista E.D. Hase

Ana Maria Trindade Grégio

Antonio Adilson Soares de Lima

Alcohol consumption was a limited risk factor for several oral conditions and, including oral cancer. This study assessed the effect of alcoholism in nuclear (NA), and cytoplasmic area (CA) and nucleus-to-cytoplasm area ratio (NA/CA) of oral squamous epithelial cells of adult male individuals. Oral smears were collected from clinically normal buccal mucosa by liquid-based exfoliative cytology of 60 individuals (30 alcohol users and 30 non-users). Glass slides were processed, stained by Papanicolaou technique and analyzed for quantitative techniques using an image analysis system (Image-Pro Plus). Mean values of NA for experimental and control groups were, respectively, 67,05±10,79μm2 and 57,91±8,12μm2 (P=0.000623). The variable CA showed the following mean values: experimental group = 2313,99±231,28μm2 and control group = 2122,95±215,71μm2 (P=0.001973). The mean value for NA/CA in both experimental and control groups was 0.2 (P=0.2182). This study revealed that alcoholism was able to induce significantly changes on the oral epithelial cells. Since this drug is normally used in association with others risk factors for oral cancer (tobacco), alcohol abusers should be submitted frequently to preventive oral exams.

Tatsuya Nakayama Dan Takeuchi T. Matsumura Kazunori Oishi

Streptococcus suis is an emerging zoonotic agent. This study aimed to investigate whether S. suis is likely to translocate across the intestines of human hosts who have liver disease and/or consume alcohol. Both the alcoholism and cirrhosis models exhibited high mRNA expression of TGF and collagen1, but only the cirrhosis model had fibrosis in the liver. After both models were infected with S. suis, significantly different concentrations of S. suis were detected in the blood and brains of the alcoholism model (Blood: 36.4%; Brain: 31.8%) and the cirrhosis model (Blood: 62.5%; Brain: 62.5%) compared to the concentrations in the healthy mice (Blood: 15.4%; Brain: 0%). Trans-epithelial electrical resistance (TER) was used to examine the Caco-2 cells in the in vitro that had an S. suisinfection combined with 1% ethanol. Although the ethanol did not influence the Caco-2 cells' barriers, it did rapidly decrease the barriers' TER value and then their E-cadherin compared to the infected Caco-2 cells without the ethanol treatment. Immunofluorescence also indicated that the barriers of the Caco-2 cells treated with ethanol were disrupted and that S. suis translocated from the apical to the basolateral side. This study demonstrated that alcohol consumption helped S. suis to translocate.

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.

Beata Keremi

Zsolt Lohinai

Peter Komora

Gabor Varga

The pentadecapeptide BPC 157 has been shown to have anti-inflammatory and wound healing effects on multiple target tissues and organs. The purpose of the present study was to investigate the effect of BPC 157 on inflammation and bone resorption in experimental periodontitis in rats. First the acute effect of BPC was tested on gingival blood flow by laser doppler flowmetry. Then periodontitis was produced by a silk ligature placed around the lower left first molar. Rats were treated with BPC 157 (once daily for 12 days) or vehicle. At day 13, the gingivomucosal tissues encircling the molars were removed on both sides. Inflammation was assessed by Evans blue plasma extravasation technique and by histology. Alveolar bone loss was analyzed by microCT. BPC 157 had no effect on gingivomucosal blood flow. Twelve day ligature caused a significantly increased Evans blue extravasation in the gingivomucosal tissue, histological signs of inflammation, and alveolar bone destruction. BPC 157 treatment significantly reduced both plasma extravasation, histological alterations and alveolar bone resorption. In conclusion, systemic application of BPC 157 does not alter blood circulation in healthy gingiva. Chronic application of the peptide has potent antiinflammatory effects on periodontal tissues in ligature induced periodontitis in rats. Taken together, this proof of concept study suggests that BPC 157 may represent a new peptide candidate in the treatment of periodontal disease.

Spomenko Ilic Domagoj Drmic

Kamelija Zarkovic

Predrag Sikiric

Chronic ibuprofen (0.4 g/kg intraperitoneally, once daily for 4 weeks) evidenced a series of pathologies, not previously reported in ibuprofen-dosed rats, namely hepatic encephalopathy, gastric lesions, hepatomegaly, increased AST and ALT serum values with prolonged sedation/unconsciousness, and weight loss. In particular, ibuprofen toxicity was brain edema, particularly in the cerebellum, with the white matter being more affected than in gray matter. In addition, damaged and red neurons, in the absence of anti-inflammatory reaction was observed, particularly in the cerebral cortex and cerebellar nuclei, but was also present although to a lesser extent in the hippocampus, dentate nucleus and Purkinje cells. An anti-ulcer peptide shown to have no toxicity, the stable gastric pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, MW 1419, 10 μg, 10 ng/kg) inhibited the pathology seen with ibuprofen (i) when given intraperitoneally, immediately after ibuprofen daily or (ii) when given in drinking water (0.16 μg, 0.16 ng/ml). Counteracted were all adverse effects, such as hepatic encephalopathy, the gastric lesions, hepatomegaly, increased liver serum values. In addition, BPC 157 treated rats showed no behavioral disturbances and maintained normal weight gain. Thus, apart from efficacy in inflammatory bowel disease and various wound treatments, BPC 157 was also effective when given after ibuprofen.

Alenka Boban Blagaic Mirela Mirt

Vladimir Blagaić

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.

Mere Martinez

Flora Milton S A de Oliveira

Francisco Eduardo Martinez

The present study analyzed the toxic effects of chronic alcohol ingestion on the ultrastructure of the lining epithelium of the hard palatine mucosa of the rodent Calomys callosus, in order to contribute to the understanding of the consequences of alcohol abuse for the morphology of the digestive system. Twenty-six adult animals aged three months were divided into two experimental groups. The control group received a solid diet and tap water, and the alcoholic group received the same solid diet and ethanol P.A. diluted 20% in water (v/v). After 120 days of treatment, all animals were anaesthetised, weighed and sacrificed. At the end of treatment, mean body weight did not differ between control and alcoholic animals. The epithelial cells of the alcoholic group showed many alterations such as the presence of lipid droplets, nuclei in corneum layer, nuclei with increase peripheral chromatin and greater electron density, altered mitochondria, and intense dilatation of the intercellular spaces. It was concluded that 20% ethanol provokes marked ultrastructural lesions in the hard palatine mucosa.

Alenka Boban Blagaic

Vladimir Blagaić Zeljko Romic

Predrag Sikiric

Alcohol disturbances, NO stimulation (by the NO-precursor L-arginine), and/or NO-synthesis blockade (by N(G)-nitro-L-arginine methyl ester, i.e. L-NAME) were challenged with stable gastric pentadecapeptide BPC 157, which inhibits both acute alcohol intoxication and alcohol withdrawal symptoms. Mice received intraperitoneally (i.p.) BPC 157 (10 microg/kg), L-NAME (10 mg/kg), and L-arginine (400 mg/kg), alone or in combination, 5 minutes before or after acute ethanol (4 g/kg i.p.) intoxication or after 0, 3, or 7 hours of withdrawal after drinking 20% alcohol for 13 days. BPC 157 rapidly opposes the strongest disturbance presentations in acute intoxication (sustained ethanol anesthesia, complete loss of righting reflex, no reaction to external stimuli, hypothermia, 25% mortality) and withdrawal (prominent seizures). NO-agents: Aggravation of acute alcohol intoxication and opposition to withdrawal are common, but the later intervals affected by L-arginine and the action throughout the experiment by L-NAME are distinctive. Given together, L-arginine and L-NAME counteract each other, while either the "L-NAME presentation" (acute intoxication) or the "L-arginine presentation" (withdrawal) predominates. BPC157+NO-agent: In acute intoxication (L-NAME predominating in NO-system functioning to aggravate intoxication), both BPC157+L-NAME and BPC157+L-arginine follow the presentation of L-NAME, but without worsened mortality. In withdrawal (L-arginine predominating in NO-system functioning to oppose disturbance symptoms), BPC157+L-NAME follows the presentation of L-NAME, while BPC 157+L-arginine imitates that of L-arginine. The relationships among pentadecapeptide BPC 157, the NO-system, acute alcohol intoxication, and opposed withdrawal may be important, presenting pentadecapeptide BPC 157 as a suitable alcohol antagonist.

G.S. Reis P F F Pinheiro

Mere Martinez

Francisco Eduardo Martinez

The effects of chronic alcohol ingestion on the structure of the glandular epithelium of the seminal vesicle of the rodent Calomys callosus were analyzed in 24 adult animals aged 3 months divided into three experimental groups. The control group received a solid diet and tap water, the alcoholic group received the same solid diet and ethanol P.A. diluted 20% in water (v/v) for 4 months. The abstinent group received the same liquid diet of the alcoholic one for the same period and after that the alcoholic diet was changed by water for a period of 3 months. After treatment, all animals were anesthetized, weighed and sacrificed. At the end of treatment, mean body weight did not differ between animal groups. The glandular epithelial cells of the alcoholic and abstinent groups showed atrophy and ultrastructural alterations such as the presence of altered nuclei, intense dilatation of the cisterns of the granular endoplasmic reticulum, intense digestive vacuoles and lipid droplets. Ethanol ingestion provokes marked lesions on the epithelium of the seminal vesicle probably interfering on the glandular secretion.

Mere Martinez

Flora Milton S A de Oliveira

Francisco Eduardo Martinez

The objective of the present study was to assess the possible toxic effects of chronic alcohol ingestion on the ultrastructure of the glandular epithelium of the prostate of the rodent Calomys callosus, in order to contribute to the understanding of the consequences of alcohol abuse for the morphology of the male reproductive apparatus. Sixteen adult animals aged three months were divided into two experimental groups. The control group received a solid diet and tap water, and the alcoholic group received the same solid diet and ethanol P.A. diluted 20% in water (v/v). After 120 days of treatment, all animals were anesthetized, weighed and sacrificed. At the end of treatment, mean body weight did not differ between control and alcoholic animals. The prostate epithelial cells of the alcoholic group showed intense atrophy and ultrastructural alterations such as the presence of lipid droplets, altered nuclei, ruptured mitochondrial cristae, and intense dilatation of the cisterns of the granular endoplasmic reticulum. It was concluded that 20% ethanol provokes marked lesions on the epithelium of the prostate probably interfering on the glandular secretion.

Nikola Jelovac

Predrag Sikiric Rudolf Rucman J Perić

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.

Martina Lovric Bencic

Predrag Sikiric Jadranka Šeparović Hanževački

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.

Predrag Sikiric

Sven Seiwerth

Zeljko Grabarevic

Brkic Tomislav

The protection of stomach and duodenum in conjecture with anti-inflammatory effect was demonstrated for a novel 15 amino acid peptide, coded BPC 157, a fragment of the recently discovered gastric juice peptide BPC. BPC 157 (i.p./i.g.) was investigated in rats in comparison with several reference standards in three experimental ulcer models (48 h-restriant stress, subcutaneous cysteamine, intragastrical 96% ethanol ulcer tests) (pre-/co-/post-treatment). Only BPC 157 regimes were consistently effective in all of the tested models. On the other hand, bromocriptine, amantadine, famotidine, cimetidine and somatostatin were in effective (restraint stress). A dose-dependent protection (cysteamine) and/or partial positive effect (related to treatment conditions) (ethanol), was obtained with glucagon, NPY and secretin whereas CCK/26– 30/ was not effective. Based on Monastral blue studies BPC 157 beneficial effect appears to be related to a strong endothelial protection.

Ingrid Prkacin

Gorana Aralica

Darko Perovic Zoran Ivasović

Unlike severe gastric damage acutely induced by ethanol administration in rat, the ulcerogenic effect of chronic alcohol administration (3.03 g/kg b.w. or 7.28 g/kg b.w.) given in drinking water, producing liver lesions and portal hypertension, is far less investigated. Therefore, focus was on the antiulcer effect of the gastric pentadecapeptide BPC 157, GEPPPGKPADDAGLV, M.W. 1419, known to have a beneficial effect in variety of gastrointestinal lesions models (10 μg or 10 ng/kg b.w. i.p. or i.g.), ranitidine (10 mg/kg b.w. i.g.) and propranol (10 mg/kg b.w. i.g.) or saline (5 ml/kg b.w. i.p./i.g.; control). They were given once daily (1) throughout 10 days preceding alcohol consumption, (2) since beginning of alcohol drinking till the end of the study, (3) throughout the last month of alcohol consumption, 2 months after alcohol drinking had been initiated. Gastric lesions were assessed, at the end of 3 months drinking [(1), (2)] or with respect to therapeutic effect of medication before medication or at the end of therapy. Pentadecapeptide BPC 157, ranitidine and propranolol may prevent gastric lesion development if given prophylactically, before alcohol drinking. Likewise, they attenuate the lesion appearance given once daily throughout the drinking period. Importantly, when given therapeutically, they may antagonize otherwise pertinent lesion presence in stomach mucosa of the drinking rats. Thus, these results demonstrate that pentadecapeptide BPC 157, ranitidine and propranol may prevent, attenuate or reverse the gastric lesions appearance in chronically alcohol drinking rats, and may be used for further therapy, while the other studies showed that their effect (except to ranitidine) is parallel with their beneficial effect on liver lesion and portal hypertension.

Michael J Mckinley

Brian J Oldfield

Unlike circulating steroid hormones, which have a relatively unhindered passage into the central nervous system, blood-borne peptides are usually restricted by the blood–brain barrier. Some circulating peptides, such as angiotensin II, atrial natriuretic peptide and relaxin, influence central neural pathways subserving cardiovascular and body fluid homeostasis by acting on neurons in the subfornical organ, organum vasculosum of the lamina terminalis and area postrema, all of which lack a blood–brain barrier. There are some circulating peptides such as insulin and leptin that are transported from the bloodstream across cerebral blood vessel walls into sites in the hypothalamus that have appropriate neural connections to influence food intake and sympathetic control of brown fat.

Sandor Szabo Jerry S. Trier A Brown J Schnoor

The hypothesis that vascular injury contributes to the development of hemorrhagic erosions after intragastric administration of ethanol has been examined in the rat using vascular tracers. Extravasation of intravenously injected Evans blue into the gastric wall and into gastric contents was used as an indicator of vascular permeability. India ink and monastral blue, which label damaged blood vessels, were used to demonstrate vascular injury morphologically. Intragastric instillation of 75% and 100% ethanol induced increased vascular permeability within 1-3 min and resulted in monastral blue labeling of vessels in 13% and 17%, respectively, of the glandular mucosa within 1 min. After 1 h of 100% ethanol exposure, the areal density of monastral blue-stained blood vessels did not increase compared with that seen at 1 min, but the areal density of grossly visible hemorrhagic lesions increased strikingly and approximated that of vessel staining. The hemorrhagic erosions consistently occurred in regions of glandular mucosa where vessels were stained with monastral blue. Pretreatment with prostaglandin F2 beta or cysteamine reduced ethanol-induced Evans blue extravasation and monastral blue staining of mucosal blood vessels but did not reduce histologic evidence of gastric surface cell damage in the glandular mucosa. As increased vascular permeability and morphologically detectable vascular lesions consistently preceded the development of grossly visible hemorrhagic erosions in the glandular mucosa, we suggest that vascular injury is an early pathogenetic factor in the development of ethanol-induced gastric hemorrhagic erosions. The data also indicate that the degree of vascular damage, unlike the injury to surface epithelial cells, is reduced by pretreatment with prostaglandin F2 beta or the sulfhydryl cysteamine.

J.R. Grogan M.S. Kochar

The link between alcohol and hypertension is well established, yet the mechanism through which alcohol raises blood pressure remains elusive. Possible mechanisms include an imbalance of the central nervous system, impairment of the baroreceptors, an increase of sympathetic activity, stimulation of the renin-angiotensin-aldosterone system, an increase in cortisol levels, an increase of intracellular calcium levels with a subsequent increase in vascular reactivity, stimulation of the endothelium to release endothelin or inhibition of endothelium-dependent nitric oxide production, and chronic subclinical withdrawal. For control of hypertension, cessation or at least reduction of alcohol intake is the first step. Pharmacologic treatment should be withheld until after 2 to 4 weeks of abstinence from alcohol. Alcoholism can result in autonomic neuropathy and cardiomyopathy that can lead to a fall in blood pressure. We believe that angiotensin-converting enzyme inhibitors and calcium channel blockers may be the most appropriate pharmacologic treatment.

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.

Michael L. Adams

Theodore J Cicero

Nitric oxide is an important messenger in the central nervous system and several types of evidence suggest that it mediates various alcohol effects. Treatment with a nitric oxide synthase inhibitor enhances the acute central depressant or anesthetic effect of alcohol and decreases some stimulatory effects of alcohol withdrawal after chronic alcohol treatment. Conversely, treatment with a nitric oxide donor inhibits the anesthetic effect of alcohol, blocks the effect of the nitric oxide synthase inhibitor on alcohol anesthesia, and enhances the severity of some alcohol withdrawal signs. These results indicate that changes in nitric oxide synthesis mediate some aspects of alcohol intoxication and withdrawal and that nitric oxide systems represent an important therapeutic target for the development of agents to treat alcoholism and alcohol intoxication.

F Fadda Z L Rossetti

In this review first we evaluate evidence on the role of the neurobiological alterations induced by chronic ethanol consumption in the development of ethanol tolerance, dependence and withdrawal. Secondly, we describe the neuropathological consequences of chronic ethanol on cognitive functions and on brain structures. Chronic alcohol consumption can induce alterations in the function and morphology of most if not all brain systems and structures. While tolerance mechanisms are unlikely to contribute to the neuroadaptive changes associated with ethanol dependence, it is otherwise clear that repeated high, intoxicating doses of ethanol trigger those neuroadaptive processes that lead to dependence and contribute to the manifestation of the abstinence syndrome upon withdrawal. An unbalance between inhibitory and excitatory neurotransmission is the most prominent neuroadaptive process induced by chronic ethanol consumption. Due to the diffuse glutamatergic innervation to all brain structures, the neuroadaptive alterations in excitatory neurotransmission can affect the function of most if not all of neurotransmitter systems. The expression of the withdrawal syndrome is the major causal factor for the onset and development of the neuropathological alterations. This suggests a link between the neuroadaptive mechanisms underlying the development of ethanol dependence and those underlying the functional and structural alterations induced by chronic ethanol. In animals and humans, specific alterations occur in the function and morphology of the diencephalon, medial temporal lobe structures, basal forebrain, frontal cortex and cerebellum, while other subcortical structures, such as the caudate nucleus, seem to be relatively spared. The neuropathological alterations in the function of mesencephalic and cortical structures are correlated with impairments in cognitive processes. In the brain of alcoholics, the prefrontal cortex and its subterritories seem particularly vulnerable to chronic ethanol, whether Korsakoff's syndrome is present or not. Due to the role of these cortical structures in cognitive functions and in the control of motivated behavior, functional alterations in this brain area may play an important role in the onset and development of alcoholism.

Barbara Malinowska Dorota Napiórkowska-Pawlak

Robert Pawlak

Manfred Göthert

The aim of the present study was to examine the influence of ifenprodil (a non-competitive NMDA receptor antagonist which also blocks 5-HT3 receptors and alpha1-adrenoceptors) on the effects of ethanol in the mouse in vivo and to elucidate the role of various receptors in these actions. The ethanol (4 g/kg i.p.)-induced sleeping time was shortened by ifenprodil 1 mg/kg but was not affected by ifenprodil 0.3 mg/kg, the 5-HT3 receptor antagonist ondansetron 0.03 mg/kg and the non-competitive NMDA receptor antagonist MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cycloheptan-5,10-imine maleate) 0.01 mg/kg. Ifenprodil 10 mg/kg mimicked the alpha1-adrenoceptor antagonist prazosin 1 mg/kg in that it prolonged the hypnotic response to ethanol (no additive effect when both drugs were given in combination); this is compatible with an involvement of alpha1-adrenoceptors in this effect of ifenprodil. Chronic exposure to ethanol (7%) induced physical dependence. The severity of ethanol withdrawal was suppressed by ifenprodil 1 and 10 mg/kg. In conclusion, ifenprodil influences ethanol-related changes in mouse behaviour and may prove to be useful in the treatment of alcoholism.

Nikola Jelovac

Predrag Sikiric Rudolf Rucman

Ingrid Prkacin

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.

Predrag Sikiric

Anton Marović Wendy Matoz Vladimir Hahn

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.

Ingrid Prkacin Jadranka Separovic

Gorana Aralica

Neven Kokic

Liver lesions and portal hypertension in rats, following chronic alcohol administration, are a particular target for therapy. Portal hypertension (mm Hg) assessed directly into the portal vein, and liver lesions induced by 7.28 g/kg b.w. of alcohol given in drinking water for 3 months, were counteracted by a stable gastric pentadecapeptide BPC 157, GEPPPGKPADDAGLV, M.W. 1419, known to have a beneficial effect in a variety of models of gastrointestinal or liver lesions (10 microg or 10 ng/kg b.w. i.p. or i.g.) and propranolol (10 mg/kg b.w. i.g.), but not ranitidine (10 mg/kg b.w. i.g.) or saline (5 ml/kg b.w. i.p./i.g.; control). The medication (once daily) was throughout either the whole 3 months period (1) or the last month only (2) (last application 24 h before sacrifice). In the background of 7.28 g/kg/daily alcohol regimen similar lesions values were assessed in control rats following alcohol consumption, after 2 or 3 months of drinking. Both prophylactic and therapeutic effects were shown. After a period of 2 or 3 months, in all control saline [intragastrically (i.g.) or intraperitoneally (i.p.)] treated rats, the applied alcohol regimen consistently induced a significant rise of portal blood pressure values over values noted in healthy rats. In rats that received gastric pentadecapeptide BPC 157 or propranolol the otherwise raised portal pressure was reduced to the values noted in healthy rats. Besides, a raised surface area (microm(2)) and increased circumference (microm) of hepatocyte or hepatocyte nucleus [HE staining, measured using PC-compatible program ISSA (VAMS, Zagreb, Croatia)] and an advanced steatosis [scored (0-4), Oil Red staining] (on 100 randomly assigned hepatocytes per each liver), an increased liver weight, all together parallel a raised portal pressure in controls. Some of them were completely eliminated (not different from healthy rats, i.e. portal pressure, the circumference and area of hepatocytes, liver weight), while others were markedly attenuated (values less than in drinking controls, still higher than in healthy rats, i.e. circumference and area of hepatocytes nucleus). On the other hand, ranitidine application attenuated only steatosis development. In summary, despite continuous chronic alcohol drinking, pentadecapeptide BPC 157, and propranolol may prevent portal hypertension as well as reverse already established portal hypertension along with related liver disturbances.

Predrag Sikiric

Nikola Jelovac Andjelka Jelovac-Gjeldum Tihomil Ziger

To study anxiolytic effect of a gastric pentadecapeptide, BPC-157. In shock probe/burying test, pentadecapeptide BPC-157 (10 microg/kg, 10 ng/kg, ip), diazepam (0.075, 0.0375 mg/kg, ip), and an equivolume of saline (5 mL/kg, ip) were given at 30 min prior test. In light/dark test, the same dosage of diazepam, BPC-157, and saline were given at 45 min prior procedure. Shock probe/burying test: rats treated with either diazepam or pentadecapeptide BPC-157 were much less afraid after the shock: almost not burying and the total time spent in burying was clearly less than in controls. However, while in the diazepam treated rats the number of shocks received increased over control values, in pentadecapeptide BPC-157 treated groups the number of shocks remained not modified compared with the control values. Light/dark test: after exposure to the intense light, diazepam treated mice had longer latencies of crossing to the dark compartment, a greater number of crossing and a greater number of exploratory rearing, and spent longer time in the light compartment, as compared to the control mice, while BPC-157 mice had a similar behavior to that of the control mice. In contrast with the effect in light area, in dark zone diazepam produced no change with respect to controls, while BPC-157 (10 microg/kg) mice had a greater number of crossing and a greater number of exploratory rearing. Both diazepam and BPC-157 displayed a bidirectional effect, but the activity of pentadecapeptide BPC-157 was particular, and different from diazepam.

Predrag Sikiric

Nikola Jelovac Andjelka Jelovac-Gjeldum

Slaven Babić

To investigate the effect of pentadecapeptide BPC 157 on chronic exposure to amphetamine in rats, particularly the changes commonly referred in chronic amphetamine studies as tolerance (lesser grade of stereotyped behavior, without increased excitability) and reverse tolerance (ie, prominent stereotyped behavior and heightened startle response upon late amphetamine challenges). After initial application (initial single dose-regimen), amphetamine (10 mg/kg,ip) was given once daily till d 5 (continuous administration-regimen), and thereafter on d 8, 16, and 46 (intermittent administration regimen). Fo r stereotyped behavior and heightened startle response the observation period was 120 min after amphetamine application, and each animal was observed for 10 s in 5 min intervals. Pentadecapeptide BPC 157 (10 microg/kg or 10 ng/k g, ip) or saline (5.0 mL/kg, ip) were given only at the beginning of the experiment, simultaneously with the initial dose of amphetamine. In relation to applied initial-single/continuous/intermittent amphetamine applications regimen, the control amphetamine rats throughout the experiment showed the changes in stereotyped behavior and heightened startle response, increment or decrement, commonly explained in chronic amphetamine studies as tolerance and reverse tolerance. After t he initial application of the amphetamine, the higher BPC 157 dosage apparently attenuated the stereotyped behavior, while the lower dosage of BPC 157 did not reach a statistical significance. Considering the forthcoming amphetamine challenges, in the rats initially treated with pentadecapeptide BPC 157, either 10 microg- or 10 ng-dose, at the time of the first application of amphetamine, the stereotyped behavior remains to be attenuated after all additional amphetamine challenges (on d 2-5, 8, 16, and 46). This attenuation was not limited to stereotyped behavior only. After the initial application of the amphetamine the heighten ed startle response was also apparently mitigated in rats receiving the BPC 157 dosage, either higher or lower. Later, confronted with the forthcoming amphetamine challenges, they showed apparently less abnormal excitability at all tested points. In summary, gastric pentadecapeptide BPC 157 (ie, both microg- and ng-BPC 157 regimens) attenuated chronic amphetamine disturbances. This effect was present throughout the observation period at a statistically significant level. Therefore, it seems that this gastric pentadecapeptide BPC 157 has a modulatory effect on dopamine system, and it could be used in chronic amphetamine disturbances.

Mark Egli

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-Sladojev D Seveljevic-Jaran M Kolega D Erceg Z Krznaric

Veljaca, M., Krnic, Z., Brajsa, K., Mildner, B., Pavic-Sladojev, D., Seveljevic-Jaran, D., Kolega, M., Erceg, D., Krznaric, Z., 2002. The development of PL 14736 for treatment of inflammatory bowel disease. IUPHAR-GI Section Symposium, Honolulu, Hawaii, 13-15, O-32. Boban Blagaic et al. / European Journal of Pharmacology 499 (2004) 285–290

Reduction of Doppler shift of otherwise increased blood flow velocity in v. cava inferior and v. portae of chronically alcohol drinking portal hypertensive rats by gastric pentadecapeptide BPC 157 (PL-10)

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