Pentadecapeptide BPC 157 and the central nervous system

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Abstract

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.

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482

|NEURAL REGENERATION RESEARCH|Vol 17|No. 3|March 2022

Pentadecapepde BPC 157 and the central nervous

system

Jakša Vukojević1, *, Marija Milavić2, Darko Perović1, Spomenko Ilić1,

Andrea Zemba Čilić3, Nataša Đuran4, Sanja Štrbe3, Zoran Zoričić5, Igor Filipčić6,

Petrana Brečić4, Sven Seiverth2, Predrag Sikirić1

Abstract

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.

Key Words: BPC 157; central nervous system; cytoprotection; injury; nitric oxide system;

peptide; regeneration

hps://doi.org/10.4103/1673-5374.320969

Date of submission: October 29, 2020

Date of decision: December 8, 2020

Date of acceptance: March 8, 2021

Date of web publicaon: August 4, 2021

Introducon

The pleiotropic beneficial effects of the stable gastric

pentadecapeptide BPC 157 have been reported in several

organ systems (Sikiric et al., 2013, 2018, 2020a, b; Seiwerth

et al., 2014, 2018; Kang et al., 2018; Gwyer et al., 2019; Park

et al., 2020) (for an illustration; Additional Table 1). In this

review, we focus on the eects of BPC 157 in central nervous

system (CNS) pathology, with a specific focus on three very

recent studies that highlight the essential role of the gut-

brain axis in therapy application for CNS disorders (Perovic

et al., 2019; Vukojevic et al., 2020; Zemba Cilic et al., 2021).

Vukojevic et al. (2020) examined the therapeuc eects of BPC

157 in rats subjected to stroke and hippocampal ischemia/

reperfusion injuries. Zemba Cilic et al. (2021) explored how

BPC 157 can prevent catalepsy induced by L-NG-nitro arginine

methyl ester (L-NAME) and haloperidol and counteracts

decits in acute and chronic rat models resembling ‘posive-

like’ schizophrenia symptoms. Finally, Perovic et al. (2019)

investigated the beneficial effects exerted by BPC 157 after

rat spinal cord compression, namely advanced healing and

funconal recovery (counteracted tail paralysis).

BPC 157 is a native gastric pentadecapeptide that is non-

toxic and has profound cytoprotective activity; it has been

used in ulcerative colitis and multiple sclerosis trials (Sikiric

et al., 2013, 2018, 2020a, b; Seiwerth et al., 2014, 2018;

Kang et al., 2018; Gwyer et al., 2019; Park et al., 2020).

In human gastric juice, BPC 157 is stable for more than

24 hours (Veljaca et al., 1995), and thus it has good oral

bioavailability (always given alone) and beneficial effects in

the enre gastrointesnal tract (Seiwerth et al., 2014, 2018;

Kang et al., 2018; Sikiric et al., 2018, 2020a, b; Gwyer et al.,

2019; Park et al., 2020). Furthermore, there is no need for

carrier(s); this is an important distinction from the other

standard peptides, which are functionally dependent on the

addion of carrier(s) (Seiwerth et al., 2018) or are otherwise

rapidly destroyed in human gastric juice (Veljaca et al., 1995).

Consequently, stable BPC 157 is suggested to be a mediator

of Robert’s cytoprotection, which maintains the integrity of

Review

1Department of Pharmacology, Medical School, University of Zagreb, Zagreb, Croaa; 2Department of Pathology, Medical School, University of Zagreb, Zagreb,

Croaa; 3University Clinical Hospital Center “Zagreb”, Zagreb, Croaa; 4University Psychiatric Hospital “Vrapče”, Zagreb, Croaa; 5University Clinical Hospital

Center “Sestre Milosrdnice”, Zagreb, Croaa; 6Psychiatric Hospital “Sve Ivan”, Zagreb, Croaa

*Correspondence to: Jakša Vukojević, MD, PhD, [email protected].

hps://orcid.org/0000-0003-4215-6743 (Jakša Vukojević)

How to cite this article: Vukojević J, Milavić M, Perović D, Ilić S, Čilić AZ, Đuran N, Štrbe S, Zoričić Z, Filipčić I, Brečić P, Seiverth S, Sikirić P (2022)

Pentadecapepde BPC 157 and the central nervous system. Neural Regen Res 17(3):482-487.

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NEURAL REGENERATION RESEARCH|Vol 17|No. 3|March 2022|483

gastrointesnal mucosa (Seiwerth et al., 2014, 2018; Kang et

al., 2018; Sikiric et al., 2018, 2020a, b; Gwyer et al., 2019; Park

et al., 2020). We suggest that the contribution of BPC 157

to Robert’s cytoprotecon – that is, the ability to counteract

fundamental alcohol-induced gastric lesions, which Robert

called cytoprotection – and the ability to counteract lesions

arising from the direct injurious contact of the noxious agent

with the cell represent the peripheral connecon between the

gut and the brain axis.

Search Strategy and Selecon Criteria

Studies cited in this review, which were published in the

period from 1995 to 2020, were searched on the PubMed and

the Google scholar database using the following keywords:

BPC, BPC 157, pentadecapepde BPC.

BPC 157 and Brain Lesions

In our recent study, we found that BPC 157 has a direct

therapeutic effect in rats after a stroke (i.e., counteracts

the injuries due to hippocampal ischemia/reperfusion).

Specifically, BPC 157 was given after bilateral clamping of

the common carotid arteries for 20 minutes, followed by

reperfusion (Vukojevic et al., 2020). In the rats subjected to

ischemia, BPC 157 was administered during reperfusion; it

counteracted both early and delayed neural damage (i.e.,

24 and 72 hours after reperfusion). In addition, BPC 157

promoted full funconal recovery; this compound ameliorated

the declines in several behavioral tasks: the Morris water

maze, inclined beam-walking, and lateral push tests (Vukojevic

et al., 2020). We also examined changes in messenger RNA

(mRNA) expression in the brain 1 and 24 hours aer the injury

to determine the potenal BPC 157 mechanism of acon. BPC

157 treatment led to the upregulaon of Egr1, Akt1, Kras, Src,

Foxo, Srf, Vegfr2, Nos3, and Nos1 and the downregulaon of

Nos2 and Nfkb compared with untreated rats (Mapk1 was

not acvated) (Vukojevic et al., 2020). The marked Egr1 and

Vegfr2 upregulaon suggests that BPC 157 has vascularisaon

properties, and this mechanism likely underlies its ability to

modulate ischemia/reprofusion injury. The most interesting

nding is the strong upregulaon of Nos3, slight upregulaon

of Nos1, and suppression of Nos2 compared with control

animals. These effects may potentially provide a novel

therapeutic solution for stroke, imparting specific beneficial

effects on the CNS (i.e., for reperfusion, the amelioration of

neuronal damage and, thereby, recovery without memory,

locomotor, and coordinaon disturbances, and the expression

of the parcular genes in the hippocampus) (Vukojevic et al.,

2020).

Reinforcing our findings, BPC 157 also counteracts various

encephalopathies that appear after exposure to different

agents or noxious procedures irrespective of the affected

brain area: traumatic brain injury (Tudor et al., 2010),

selective and non-selective non-steroidal anti-inflammatory

drugs (NSAIDs; i.e., brain cyclooxygenases are a preferential

inhibitory target of paracetamol; Sikiric et al., 2013; Lojo et

al., 2016; Drmic et al., 2017), massive intestinal resection,

cuprizone-induced multiple sclerosis-like pathology, insulin

overdose, or magnesium overdose (Sikiric et al., 2013;

Medvidovic-Grubisic et al., 2017). BPC 157 can also be

applied to ameliorate concomitant convulsions due to NSAID-

induced encephalopathy (Sikiric et al. 2013) (Addional Table

1). BPC 157 treatment regimens markedly attenuate brain

damage induced by traumatic brain injury (a falling weight);

there is an improved early outcome and minimal postponed

mortality throughout the 24-hour post-injury period in mice

(Tudor et al., 2010). Ultimately, BPC 157 therapy induces an

apparent improvement: the subarachnoid and intraventricular

hemorrhage, brain lacerations, hemorrhagic laceration, and

consecuve brain edema becomes less intense (Tudor et al.,

2010). Furthermore, BPC 157 treatment promoted recovery

from severe muscle weakness that appears alongside brain

lesions (Sikiric et al., 2013; Medvidovic-Grubisic et al., 2017).

When applied directly to the brain (Belosic Halle et al., 2017),

BPC 157 may act as a possible anoxidant (Duzel et al., 2017;

Drmic et al., 2018; Kolovrat et al., 2020). Notably, BPC 157

may scavenge reacve oxygen species due to its structure: it

contains four carboxylic groups, and when they are reacvated

(by glutathione or enzymes), the antioxidant activity is very

high (Seiwerth et al., 2014, 2018; Kang et al., 2018; Sikiric et

al., 2018, 2020a, b; Gwyer et al., 2019; Park et al., 2020). In

addion, because most ssues contain BPC 157 (Seiwerth et

al., 2018), it can bind and inacvate reacve free radicals at

crucial posions not reachable by other anoxidants (Seiwerth

et al., 2014, 2018; Kang et al., 2018; Sikiric et al., 2018, 2020a,

b; Gwyer et al., 2019; Park et al., 2020).

The beneficial effects of BPC 157 on hippocampal ischemia/

reperfusion injury (caused by bilateral clamping of the

common carotid arteries) (Vukojevic et al., 2020) are

supported by the course of Robert’s cytoprotection,

originally described for intragastric absolute alcohol-induced

epithelial/endothelial injuries (Sikiric et al., 2020b), regarded

as the Virchow triad. The ability to counteract Robert’s

gastric hemorrhagic lesion – the epithelial, endothelial,

and thrombotic lesions arising from the direct, injurious

contact of a noxious agent with a cell – underscores the

cytoprotection (Szabo et al., 1986; Sikiric et al. 2020b). The

cause–consequence relationship attributes the beneficial

eects of BPC 157 with cytoprotecon and implicates a rapid

injury defense response (Sikiric et al., 2020b). BPC 157 directly

protects the endothelium (Sikiric et al., 2006). Furthermore,

aer abdominal aorta anastomosis and major vein occlusion,

BPC 157 both stops thrombosis formation and resolves

already formed thrombi (Vukojevic et al., 2018; Gojkovic et

al., 2020; Kolovrat et al., 2020). BPC 157 can also alleviate

peripheral vascular occlusion disturbances and consequent

syndromes by rapidly activating alternative bypass pathways

(Duzel et al., 2017; Drmic et al., 2018; Vukojevic et al., 2018,

2020; Berkopic et al., 2020; Gojkovic et al., 2020; Kolovrat et

al., 2020). The therapeuc eect is stable, despite connuous

ligation (occlusion), and the ligation-induced disturbances

do not reappear (Duzel et al., 2017; Vukojevic et al., 2018,

2020; Gojkovic et al., 2020; Kolovrat et al., 2020). Thereby,

the evidence has demonstrated that the advanced injurious

circle may be stopped and reversed with BPC 157 therapy.

Namely, BPC 157-treated animals exhibit more extensive and

faster reperfusion. Such recovery of vascular capacity may

be an essenal mechanism by which BPC 157 administraon

facilitates reperfusion because it counteracts all pre-existing

disturbances and markedly aenuates organ lesions (Vukojevic

et al., 2018; Kolovrat et al., 2020). Thus, it is likely that such

rapid rescue of vascular capacity may contribute to the

beneficial effects of BPC 157 on rats subjected to stroke

and hippocampal ischemia/reperfusion damage recovery

(Vukojevic et al., 2020).

There is additional evidence that BPC 157 leads to a rapid

rescue of vascular capacity. In an acute ethanol intoxicaon 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 aer ethanol intoxicaon,

rapidly counteracts the above-mentioned negative effects

(Blagaic et al., 2004). Furthermore, BPC 157, when given aer

abrupt cessation of ethanol – continuous drinking of 20%

alcohol drinking for 13 days, with a provocaon on day 14 –

attenuates withdrawal (assessed over 24 hours) (Blagaic et

al., 2004). BPC 157 maintains vascular integrity to counteract

alcohol leakage to ssues (Sikiric et al., 2020b), an eect that

substantiates the previously emphasized evidence that BPC

157 directly protects the endothelium (Sikiric et al., 2006;

2018), which is a hallmark in cytoprotecon studies (Szabo et

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484

|NEURAL REGENERATION RESEARCH|Vol 17|No. 3|March 2022

al., 1986). Consequently, researchers have consistently shown

that BPC 157 strongly counteracts the effects of alcohol

administered into the rat stomach, namely the rapid damage

to the endothelium (Sikiric et al., 2006; 2018; Becejac et al.,

2018). In addition, BPC 157 is a strong membrane stabilizer

(Park et al., 2020). Therefore, BPC 157 also counteracts portal

hypertension induced by chronic alcohol consumpon. Based

on the role that BPC 157 may play a role in antagonizing the

eects of alcohol, Zemba et al. (2015) showed that BPC 157

can mitigate the general anesthetic potency of thiopental

as well as the more prolonged anesthesia induced by the

L-NAME/thiopental combinaon.

BPC 157 and Behavioral Disorders

Researchers have increasingly reported the importance of

the nitric oxide (NO) system in the therapy of schizophrenia

(MacKay et al., 2010) and extrapyramidal deficits linked

with the more severe psychiatric symptoms (Weng et al.,

2019), such as haloperidol-induced catalepsy (Jelovac et al.,

1999a). Recently, Zemba Cilic et al. (2021) demonstrated

that BPC 157 counteracts catalepsy induced by L-NAME and

haloperidol as well as the deficits of acute and chronic rat

models resembling “positive-like” schizophrenia symptoms

in rat models (Moore and Grace, 2002; Rung et al., 2005).

That combined counteracon may be the key to resolve the

complex relaonship between the NO system, amphetamine

and apomorphine (the application of dopaminergic agents),

MK-801 (a non-competitive antagonist of the N-methyl-

D-aspartate receptor), and chronic methamphetamine

administration (to induce sensitivity) (Zemba Cilic et al.,

2021). This finding implicates interactions between BPC

157, dopamine, glutamate, and NO, which seem to be well-

controlled by BPC 157 administration (Zemba Cilic et al.,

2021). BPC 157 application resolves the unusual parallel

matching action in counteracting the amphetamine-induced

disturbances that L-NAME and L-arginine may cause, as well as

the decits in rat models resembling “posive-like” symptoms

of schizophrenia (Przewlocka et al., 1996). We idened two

distinctive NO system responses. Effects induced by acute

apomorphine, chronic methamphetamine, acute MK-801,

or acute haloperidol administraon (catalepsy) are “L-NAME

non-responsive, L-arginine responsive” (Zemba Cilic et al.,

2021). Acute amphetamine-induced effects are “L-NAME

responsive, L-arginine responsive” (Zemba Cilic et al., 2021).

The fact that the NO-mediated effects are responsive to

BPC 157 (Zemba Cilic et al., 2021) may be a consequence of

the aforementioned counteracting potential of BPC 157 on

disturbances induced by dopamine (Jelovac et al., 1999a;

Sikiric et al., 2020b) and NO (Zemba et al., 2015; Kokot et

al., 2016; Duzel et al., 2017). Besides, BPC 157 counteracts

the symptoms in Parkinson’s disease rodent models

(induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

or reserpine (Zemba Cilic et al., 2021)). Likewise, BPC 157

mitigates gastric lesions induced by 1-methyl-4-phenyl-

1,2,3,6-tetrahydropyridine or reserpine (Zemba Cilic et al.,

2021). Thus, the BPC 157/dopamine relaonship exerts many

effects. It includes the interference with dopamine receptor

blockade (Jelovac et al., 1999a), the development of receptor

supersensitivity (Jelovac et al., 1999a), dopamine receptor

activation (Zemba Cilic et al., 2021), dopamine over-release

(Zemba Cilic et al., 2021), damage to nigrostriatal dopaminergic

neurons (Sikiric et al., 2020b), and depletion of dopamine

vesicles (Sikiric et al., 2020b). BPC 157 also counteracts the

adverse eects of neurolepc applicaon that appear outside

of the CNS, such as prolonged QT intervals observed with

electrocardiography (Strinic et al., 2017) or adverse eects in

the gastrointesnal tract, such as gastric lesions or sphincter

dysfunction (Belosic Halle et al., 2017). Consequently, BPC

157 might be essenal for adequate dopamine funcon, and

vice versa. Serotonin and BPC 157 show a similar relaonship

(Tohyama et al., 2004; Boban Blagaic et al., 2005). In rats, BPC

157 counteracts the symptoms of Porsolt’s depression model

and the chronic unpredictable stress depression model; it also

fully counteracts all manifestaons of serotonin syndrome and

induces acute and chronic serotonin release in specic brain

nigrostriatal regions (Tohyama et al., 2004; Boban Blagaic

et al., 2005). Thus, unlike imipramine, BPC 157 exhibits a

parcular andepressant eect, even when given systemically

(Tohyama et al., 2004; Boban Blagaic et al., 2005).

Considering the BPC 157/NO relaonship (Zemba et al., 2015;

Kokot et al., 2016; Duzel et al., 2017), studies in stomach ssue

have revealed that BPC 157 alone induces NO release, even in

a condion that precludes the eect of L-arginine (Turkovic et

al., 2004). In the most recent study, the authors reported that

BPC 157 induces NO generation in the isolated aorta, likely

through the acvaon of the Src/caveolin-1/endothelial nitric

oxide synthase pathway (Hsieh et al., 2020). Thus, there is an

advantage when using a substance (i.e, BPC 157) to modulate

the NO system. This phenomenon may counteract the

adverse effects of L-NAME, a nitric oxide synthase inhibitor,

and L-arginine, a nitric oxide synthase substrate – that is,

both L-NAME-induced hypertension and L-arginine-induced

hypotension. Researchers have investigated how this effect

may be practically translated into enhanced clinical efficacy

regarding its interactions with the NO system, based on its

particular effects seen in various models and species. There

is also a supporting analogy with its counteracting effect on

dopamine-induced adverse effects. A particular example

is an amphetamine-induced stereotypy and haloperidol-

induced catalepsy, both of which are counteracted by BPC 157

administraon (Jelovac et al., 1999a; Zemba Cilic et al., 2021).

Although animal models have possible limitations (Jones et

al., 2011), the BPC 157 mechanism of action, the BPC 157/

dopamine/glutamate/NO interacon and eects, and the safe

clinical profile of BPC 157 cannot be neglected (Seiwerth et

al., 2014, 2018; Kang et al., 2018; Sikiric et al., 2018, 2020a,

b; Gwyer et al., 2019; Park et al., 2020). These findings

suggest that BPC 157 may influence essential functions

and counteract the dysfunction underlying schizophrenia-

like symptoms (Zemba Cilic et al., 2021). A contributing

factor may be that BPC 157 increases serotonin release

in nigrostriatal brain areas (during either acute or chronic

administration, determined with highly specific alpha

methyl-L-tryptophan autoradiography measurements). This

release has a consequent antidepressant effect (including

counteracon of serotonin syndrome) and relaonships with

the serotonin system (Tohyama et al., 2004; Boban Blagaic et

al., 2005). Together with the counteracng eects of BPC 157

against ethanol exposure (Blagaic et al., 2004) and diazepam

withdrawal (Jelovac et al., 1999b), we may speculate that

BPC 157 has a particular modulatory effect, which may be

necessary for maintaining the proper functioning of several

systems.

BPC 157 is a novel and efficacious ethanol antagonist; it

always counteracts negave eects due to ethanol exposure.

Given that few pharmacological agents consistently act as

ethanol antagonists, the negative effects elicited by acute

or chronic alcohol disturbances (Blagaic et al., 2004) cannot

be modulated by traditional pharmacotherapy (for a review,

see Fadda and Rossetti, 1998). The GABAergic transmission

was long ago implicated in the regulation of dopamine-

mediated events (associated with extrapyramidal systems)

and behavior that is dependent on striatal funcons (catalepsy,

stereotypies). Hence, it is interesng that BPC 157 counteracts

GABA system disturbances, such as diazepam-induced

tolerance/withdrawal (Jelovac et al., 1999b). Perrault et al.

(1992) examined physical dependence, which is commonly

studied in similar models as increased sensivity to convulsant

challenge, in mice that were chronically treated with diazepam

for different times. After discontinuation of diazepam

conditioning, the authors examined the latency to convulse

Review

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NEURAL REGENERATION RESEARCH|Vol 17|No. 3|March 2022|485

induced by the convulsant challenge (Perrault et al., 1992).

The development of tolerance and physical dependence

are among the most serious side effects of benzodiazepine

therapy. Importantly, BPC 157 has anticonvulsant activity

against several challenges (Sikiric et al., 2013; Lozic et al.,

2020).

Boban Blagaic et al. (2009) addressed how BPC 157

application affects morphine-induced analgesia compared

with the opioid antagonist naloxone. The authors used the

hot plate test to determine how naloxone and BPC 157

counteract morphine-induced analgesia. Naloxone had

an immediate counteracting effect on morphine-induced

analgesia, but BPC 157 required more time (30 minutes) to

produce an effect (Boban Blagaic et al., 2009). Haloperidol,

a central dopamine antagonist, enhances morphine-induced

analgesia, and BPC 157 counteracts this enhancement; this

represents an additional dopamine-related effect. On the

contrary, naloxone completely abrogates the analgesic eect;

specically, the pain reacon returns to basic levels. BPC 157,

naloxone, and haloperidol per se fail to exert analgesic acon

(Boban Blagaic et al., 2009). It had been noted that in mice,

BPC 157 counteracts inflammatory and non-inflammatory,

prostaglandin-dependent and prostaglandin-independent pain

(i.e., tail pinching, acec acid, and magnesium sulfate-induced

writhing in mice). Thus, BPC 157 may specically interact with

the opioid system and the pain reaction. In rats, BPC 157,

in relation to the NO system, counteracts lidocaine-induced

adverse effects and also prolongs local anesthesia (Lozic et

al., 2020). Likewise, BPC 157 counteracts lidocaine-induced

depolarisaon in vitro (Lozic et al., 2020).

It is evident that BPC 157 has a parcularly safe prole, which

is quite distinctive from standard pharmacological agents.

Indeed, unlike neuroleptics and antidepressants, BPC 157

has a particular cardioprotective and antiarrhythmic activity

(Strinic et al., 2017; Lozic et al., 2020).

BPC 157 and Spinal Cord Injury

Perovic et al. (2019) reported that BPC 157 has a marked

therapeutic effect pertaining to the recovery of rats with a

spinal cord injury with tail paralysis (1-minute compression

injury of the sacrocaudal spinal cord [S2–Co1]). Specically, a

single intraperitoneal BPC 157 administration at 10 minutes

post-injury counteracts the negative effects. By contrast,

the spinal cord injury and tail paralysis persist in untreated

rats, assessed days, weeks, months, and a year after the

injury (Perovic et al., 2019). Of note, BPC 157 aenuates the

commonly caused damage (i.e., the substanal hemorrhagic

zone in lateral and posterior white columns with sparing

of the grey matter) (Perovic et al., 2019). Thereby, BPC 157

therapy results in evident funconal (recovered tail paralysis),

microscopic, and electrophysiologic recovery (Perovic et

al., 2019). Of note, in rats with spinal cord injury, there is

permanent reperfusion. Once BPC 157 is administered 10

minutes post-compression injury (which represents the

advanced reperfusion stage), there is continuous protection

and no spontaneous spinal cord injury-induced disturbances

reappear (Perovic et al., 2019).

All spinal cord injuries immediately provoke hemorrhage,

with subsequent death of neurons and oligodendrocytes (Fan

et al., 2016). Hence, it is conceivable that early hemostasis

may be beneficial and enable functional recovery after

spinal cord contusion in rats (Fan et al., 2016). However, the

effect exerted by BPC 157 is likely different from the simple

hemostatic effect that would attenuate spinal cord injury

(Fan et al., 2016), because BPC 157 also markedly improves

thrombocyte function in rats without affecting coagulation

factors (Stupnisek et al., 2015; Vukojevic et al., 2018; Konosic

et al., 2019). During recovery from spinal cord injury, BPC

157 also directly protects the endothelium (Sikiric et al.,

2006), alleviates peripheral vascular occlusion disturbances,

rapidly acvates alternave bypass pathways, and counteracts

venous occlusion–induced syndromes (Duzel et al., 2017;

Drmic et al., 2018; Vukojevic et al., 2018, 2020; Berkopic et

al., 2020; Gojkovic et al., 2020; Kolovrat et al., 2020). Thus,

assuming that there is a substantial venous contribution

to the spinal cord compression (Bakker et al., 2015), it is

conceivable that the reestablished blood flow mediated by

BPC 157 may undoubtedly contribute to the rapid recovery

effect (Perovic et al., 2019). Furthermore, considering that

BPC 157 promotes permanent reperfusion after spinal

cord compression, it should be noted that when BPC 157 is

given during reperfusion, it counteracts stroke induced by

bilateral clamping of the common carotid arteries. BPC 157

resolves neuronal damage and prevents memory, locomotor,

and coordination deficits (Vukojevic et al., 2020). BPC 157

apparently exerts these eects by altering gene expression in

the hippocampus (Vukojevic et al., 2020).

BPC 157 exerts multifactorial therapeutic activity in rats

subjected to spinal cord injury (Perovic et al., 2019). There

is the anti-inflammatory activity, amelioration of capsaicin-

induced somatosensory neuronal damage (Sikiric et al., 1996),

recovery of the sciac nerve aer transecon (Gjurasin et al.,

2008), and protection of cultured enteric neurons and glial

cells (Wang et al., 2019). BPC 157 also ameliorates concussive

trauma-induced brain injury (Tudor et al., 2010) and severe

encephalopathies that affect various brain areas (Sikiric et

al. 2013; Lojo et al., 2016; Drmic et al., 2017; Medvidovic-

Grubisic et al., 2017). Furthermore, BPC 157 migates other

consequences such as gastrointestinal and/or liver lesions

(Sikiric et al. 2013; Lojo et al., 2016; Drmic et al., 2017) as well

as severe muscle weakness (Medvidovic-Grubisic et al., 2017)

(Addional Table 1). In addion, BPC 157 induces healing of

mechanically severed muscles due to complete transection,

crush, and denervation injuries (Mihovil et al., 2009) and

intramuscular succinylcholine application (Stambolija et

al., 2016). These benefits include muscle function recovery

and counteraction of muscle lesions due to neuromuscular

junction failure, fasciculation, paralysis, and hyperalgesia

(Mihovil et al., 2009; Stambolija et al., 2016). BPC 157

interacts with various molecular pathways (Tkalcević et al.,

2007; Chang et al., 2011, 2014; Cesarec et al. 2013; Huang et

al., 2015; Hsieh et al., 2017, 2020; Kang et al., 2018; Vukojevic

et al., 2018, 2020; Wang et al., 2019; Park et al., 2020) and,

thereby, counteracts the increased levels of pro-inammatory

and pro-cachectic cytokines and annihilates tumor induced-

muscle cachexia (Kang et al., 2018). Finally, BPC 157 shows

intrinsic antidotal activity against the adverse effect of

lidocaine and local anesthetics (in particular, limb function

failure due to L4–L5 spinal cord intrathecal block, bradycardia

and tonic-clonic convulsions, and depolarisation of HEK293

cells) (Lozic et al., 2020).

Based on the myriad of beneficial effects mediated by BPC

157, the funconal rescue of the paralyzed tail, as well as the

mitigation of axonal and neuronal necrosis, demyelination,

and cyst formation (Perovic et al., 2019), may be the cause

or consequence of the beneficial effects of BPC 157 on

related disturbances (Seiwerth et al., 2014, 2018; Kang et al.,

2018; Sikiric et al., 2018, 2020a, b; Gwyer et al., 2019; Park

et al., 2020). Thereby, BPC 157 may impact all stages of the

secondary injury phase (Perovic et al., 2019).

In conclusion, BPC 157 exerts beneficial effects on stroke,

schizophrenia, and spinal cord injury (Perovic et al., 2019;

Vukojevic et al., 2020; Zemba Cilic et al., 2021). Researchers

have consistently demonstrated that BPC 157 exerts a myriad

of benecial eects throughout the body. There is no reason

to indicate that the benefits of BPC 157 are limited by the

validity of the ulized models and/or methodology limitaons.

Indeed, we can argue that the eecveness, easy applicability,

[Downloaded free from http://www.nrronline.org on Wednesday, October 13, 2021, IP: 161.53.104.41]

486

|NEURAL REGENERATION RESEARCH|Vol 17|No. 3|March 2022

safe clinical prole and mechanism of BPC 157 (i.e., BPC 157/

dopamine/glutamate/NO system) represent an alternative,

likely successful, future therapeuc direcon for neurological

condions. Therefore, addional studies are needed to clarify

how potenal BPC 157 therapy would specically deal with a

mechanism of action that involves multiple subcellular sites

in the CNS. The inuence on the funcon of most, if not all,

neuronal systems at the molecular, cellular, and systemic

levels should be explored. Some visceral repeve relay of the

CNS or circumventricular organs, one of the few regions in the

brain without the blood-brain barrier, is a known pathway by

which a systemically administered pepde can exert a central

eect. Thus, it must act within the gut-brain axis, regardless of

whether this acon is direct or indirect.

Author contribuons: Manuscript concepon and design: JV, PS, SS; data

collecon and literature search: DP, NĐ, SI, AZĆ, SŠ; data integraon:

MM, ZZ, IF, PB; dra manuscript preparaon: JV, SS, PS; intellectual

contribuon to the nal manuscript; MM, ZZ, IF, PB. All authors reviewed

and approved the nal version of the manuscript.

Conicts of interest: The authors declare no conicts of interest.

Financial support: None.

Copyright license agreement: The Copyright License Agreement has

been signed by all authors before publicaon.

Plagiarism check: Checked twice by iThencate.

Peer review: Externally peer reviewed.

Open access statement: This is an open access journal, and arcles

are distributed under the terms of the Creave Commons Aribuon-

NonCommercial-ShareAlike 4.0 License, which allows others to remix,

tweak, and build upon the work non-commercially, as long as appropriate

credit is given and the new creaons are licensed under the idencal

terms.

Open peer reviewers: Victor Diogenes Amaral Silva, Universidade Federal

da Bahia, Brazil; Brijesh Kumar Singh, Columbia University, USA.

Addional les:

Addional Table 1: Sever encephalophaes and BPC 157.

Addional le 1: Open peer review report 1.

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P-Reviewers: Silva VDA, Singh BK; C-Editors: Zhao M, Qiu Y; T-Editor: Jia Y

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Table 1 Sever encephalophaties and BPC 157

Study

Noxious procedure

BPC 157 regimens

Assessed injured targets, which BPC 157

therapy beneficially affected

Ilic et al., 2011a

Diclofenac

(12.5 mg/kg

intraperitoneally, once daily

for 3 days) in rats.

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).

Gastrointestinal lesions

Severe gastric and intestinal lesions

Liver lesions

Pronounced parenchymal necrosis, extensive

microvesicular steatosis, and sinusoidal dilation;

increased bilirubin, aspartate transaminase (AST),

alanine transaminase (ALT) serum values,

increased liver weight.

Brain lesions

Prolonged sedation/unconsciousness, 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.

Ilic et al., 2010

Paracetamol overdose

(5 g/kg intraperitoneally)

in rats

BPC 157 therapy (10 μg, 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).

Liver lesions

Increased ALT, AST, and ammonium serum values

precede liver lesion, hepatomegaly.

Brain lesions

Neurons presented severe damage in several brain

areas,

Significant damage became apparent, accompanied

by generalized convulsions. Edema was already

present at 25 min following paracetamol

application at the time of initiation of the

generalized convulsions.

Ilic et al., 2009

Insulin overdose (250 IU/kg

i.p.) in rats

BPC 157 (10μg/kg) given (i)

intraperitoneally or (ii)

intragastrically immediately after

insulin.

Gastrointestinal lesions

Severe gastric ulcers

Liver lesions

Hepatomegaly, fatty liver, increased AST, ALT,

amylase serum values, and liver glycogen

breakdown with profound hypoglycemia and

calcification development. Calcium deposits were

present in the blood vessel walls, hepatocytes

surrounding blood vessels, and sometimes even in

the parenchyma of the liver, mainly as linear and

only occasionally as granular accumulation.

Brain lesions

Seizures (eventually fatal), severely damaged

neurons in the cerebral cortex and hippocampus.

Drmic et al.,

2017

Celecoxib (1 g/kg b.w. ip)

in rats

Stable gastric pentadecapeptide

BPC 157 (known to inhibit these

lesions, 10 μg/kg, 10 ng/kg, or 1

ng/kg ip) and L-arginine (100

mg/kg ip), as well as NOS

blockade (L-NAME) (5 mg/kg

ip) given alone and/or combined

immediately after celecoxib.

Gastrointestinal lesions

Severe gastric lesions

Liver lesions

Marked steatosis, congestion, and necrosis at 24 h

and at 48 h, along with increased enzyme serum

values.

Brain lesions

Brain edema was commonly absent, though

damaged (balloonized) red neurons were markedly

expressed, particularly in the cerebral cortex and in

the Purkinje cells.

Ilic et al., 2011b

Chronic ibuprofen (0.4 g/kg

intraperitoneally, once daily

for 4 weeks)

Stable gastric pentadecapeptide

BPC 157 (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).

Gastrointestinal lesions

Severe gastric lesions

Liver lesions

Hepatomegaly, increased AST and ALT serum

values with, and weight loss.

Brain lesions

Prolonged sedation/unconsciousness

In particular, ibuprofen toxicity was brain edema,

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NEURAL REGENERATION RESERACH www.nrronline.org

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 were also present, although to a lesser

extent in the hippocampus, dentate nucleus, and

Purkinje cells.

Lojo et al., 2016

Immediately after

anastomosis creation, short-

bowel rats were untreated

or administered

intraperitoneal diclofenac

(12 mg/kg)

BPC 157 (10 μg/kg or 10 ng/kg),

L-NAME, 5 mg/kg, L-arginine

(100 mg/kg) alone or combined,

intraperitoneally, and assessed 24

h later.

Gastrointestinal lesions

Rats with surgery (short-bowel) alone exhibited

mild stomach/duodenum lesions, while those also

administered diclofenac showed widespread severe

lesions in the gastrointestinal tract.

Liver lesions

Rats with surgery (short-bowel) alone exhibited

considerable liver lesions, while those also

administered diclofenac showed widespread severe

liver lesions.

Brain lesions

Rats with surgery (short-bowel) alone exhibited

severe cerebral/hippocampal lesions, while those

also administered diclofenac showed widespread

severe lesions in cerebellar nuclear/Purkinje cells

and cerebrum/hippocampus.

Medvidovic-

Grubisic et al.,

2017

Magnesium sulfate (560

mg/kg intraperitoneally)

Medication (given

intraperitoneally/kg at 15 min

before magnesium) [BPC 157

(10 μg, 10 ng), L-NAME (5 mg),

L-arginine (100 mg), alone

and/or together] in rats.

Muscle weakness, muscle lesions

Severe muscle weakness and prostration decreased

muscle fibers in both quadriceps muscle and

diaphragm. Rats that received either L-NAME or

L-arginine as individual agents and then

magnesium became feeble immediately after

magnesium treatment and exhibited more muscle

weakness and prostration.

Hypermagnesemia, hyperkalemia, increased serum

enzyme values

Additionally increased hypermagnesemia, and

newly emerged hyperkalemia (L-NAME or L-

arginine).

Brain lesions

Prominent damage was observed in the cerebral

cortex (also extended to cerebellar nuclei with both

L-NAME and L-arginine).

In HEK293 cells, the increasing magnesium

concentration from 1 to 5 mM could depolarize the

cells at 1.75 ± 0.44 mV.

Klicek et al.,

2013

Multiple sclerosis suited

toxic rat model, cuprizone

(compared with standard, a

several times higher

regimen, 2.5% of diet

regimen + 1 g/kg

intragastrically/day)

BPC 157 (in drinking water 0.16

μg or 0.16 ng/mL 12 mL/d/rat +

10 μg or 10 ng/kg

intragastrically/day) till the

sacrifice at day 4.

Muscle weakness

Cerebellar ataxia and impaired forelimb function.

Control animals affected with cuprizone toxicity

spare right forelimb, and thereby react only with

one or no forelimb and have difficulty with

maintaining body balance while rearing

Brain lesions

Cuprizone-controls clearly exhibited an

exaggerated and accelerated damaging process;

nerve damage appeared in various brain areas, with

most prominent damage in the corpus callosum,

laterodorsal thalamus, nucleus reunions, anterior

horn motor neurons.

To illustrate the pleiotropic beneficial effect of the BPC 157 therapy, we summarized the BPC 157 studies of the severe encephalopathies that affect

various brain areas.

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... BPC-157 also preserves neuromuscular function by stabilizing acetylcholine receptors and nerve terminals at the neuromuscular junction (NMJ), effectively reversing paralysis induced by neuromuscular blockers such as succinylcholine and lidocaine [24,43,44]. It further maintains central nervous system homeostasis by normalizing disrupted neurotransmitter signaling involving dopamine, serotonin, and gamma-aminobutyric acid (GABA), essential for stabilizing synaptic function and ensuring neuromuscular coordination after injury or toxin exposure [43,45]. ...

... BPC-157 also preserves neuromuscular function by stabilizing acetylcholine receptors and nerve terminals at the neuromuscular junction (NMJ), effectively reversing paralysis induced by neuromuscular blockers such as succinylcholine and lidocaine [24,43,44]. It further maintains central nervous system homeostasis by normalizing disrupted neurotransmitter signaling involving dopamine, serotonin, and gamma-aminobutyric acid (GABA), essential for stabilizing synaptic function and ensuring neuromuscular coordination after injury or toxin exposure [43,45]. BPC-157 has also demonstrated the ability to normalize glutamatergic signaling, including in models of NMDA receptor overactivation [41]. ...

... Preclinical studies consistently highlight its ability to accelerate tendon, muscle, and ligament, healing, even under compromised conditions [15,20,24,26,39,53]. Its proposed mechanisms, ranging from modulation of nitric oxide signaling to stabilization of neuromuscular junctions, suggest BPC-157 may significantly enhance recovery and functional outcomes in musculoskeletal injuries [20,23,25,26,43]. In addition to its regenerative effects, animal studies and one human pilot sutdy have shown BPC-157 to be well tolerated even at high doses, with no identified toxic or lethal thresholds and no observed teratogenic, genotoxic, or anaphylactic effects [52,83]. ...

Flynn McGuire Riley Martinez

Annika Lenz

Dan Cushman

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

... On the other hand, there can be favoring the BPC 157/neurotransmitter relations. This goes with its ample range of beneficial effects, obtained within the same dose range [1][2][3][4][5][6][7][8][9][10][11]15,[27][28][29][30]33,109,124,125], as the most valuable proof of the neurotransmitter requires that the application of the chemical directly to the target cells should produce the same response observed when the chemical is naturally released from the neurons [12][13][14]. Thus, given the particularities of the observed BPC 157 therapy effect [1][2][3][4][5][6][7][8][9][10][11]15,[27][28][29][30]33,109,124,125], this final point, the equation between the exogenous effects and endogenous presence to verify endogenous presence and significance, can be a suggestive argument for the possible BPC 157/neurotransmitter relation. ...

... This goes with its ample range of beneficial effects, obtained within the same dose range [1][2][3][4][5][6][7][8][9][10][11]15,[27][28][29][30]33,109,124,125], as the most valuable proof of the neurotransmitter requires that the application of the chemical directly to the target cells should produce the same response observed when the chemical is naturally released from the neurons [12][13][14]. Thus, given the particularities of the observed BPC 157 therapy effect [1][2][3][4][5][6][7][8][9][10][11]15,[27][28][29][30]33,109,124,125], this final point, the equation between the exogenous effects and endogenous presence to verify endogenous presence and significance, can be a suggestive argument for the possible BPC 157/neurotransmitter relation. Therefore, the conceptual evidence can be summarized as follows ( Figure 1). ...

... relations with neurotransmitter activity based on the general significance of Robert's and Szabo's stress concept and Selye's stress concept leading to the pleiotropic effects by cytoprotection agent application (BPC 157 acts as a cytoprotection mediator, and thereby pleiotropic significance), and pleiotropic significance of acknowledged neurotransmitters (i.e., acetylcholine, histamine, dopamine, glutamine, glycine, GABA, noradrenaline, and adrenaline). For the stable gastric pentadecapeptide BPC 157, pleiotropic beneficial effects can be used as proof of the neurotransmitter activity [1][2][3][4][5][6][7][8][9][10][11][12][13][14][16][17][18][19][20][21][27][28][29][30][31][32]. All these points may be supported by its special interaction with various molecular pathways [8,11,75,[115][116][117][118][119][120][121][122][123], especially with the nitric oxide (NO)-system [121][122][123][124][125][126][127][128][129][130] as a whole. ...

Predrag Sikiric

Alenka Boban Blagaic Sanja Strbe

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.

... Animal studies have suggested that BPC-157 exhibits anti-inflammatory effects, with chronic dosing particularly potent against ligature-induced periodontitis in rats [36]. Notably, BPC-157 has been seen to counteract inflammatory and non-inflammatory pain in mice, and the biologic may interact with the opioid system through dopaminergic pathways to influence sensitivity to pain [48]. Therefore, BPC-157 has the potential to serve as an alternative for traditional pharmacotherapies, including steroid medications. ...

Claire Yuan Ariana Demers

Victor Silva Christopher L. Robinson

Body Protective Compound-157 (BPC-157) is a synthetic pentadecapeptide derived from gastric proteins that has demonstrated notable reparative and anti-inflammatory properties across diverse preclinical models. Experimental evidence reveals that BPC-157 supports angiogenesis, collagen synthesis, fibroblast activity, and modulation of nitric oxide pathways, contributing to enhanced healing of muscle, tendon, ligament, bone, and gastrointestinal tissue. Studies also report reduced inflammatory cytokine activity, improved microvascular integrity, and beneficial effects on pain modulation through peripheral and dopaminergic mechanisms. Although animal data indicate favorable safety and pharmacokinetics, human research remains limited to small pilot studies investigating musculoskeletal pain, interstitial cystitis, and intravenous administration, all suggesting potential therapeutic value without reported major adverse effects. However, inconsistent preparation standards, limited clinical validation, and regulatory restrictions underscore the need for rigorous controlled trials. BPC-157 remains a promising candidate for regenerative medicine, yet comprehensive evaluation is required before clinical translation can be recommended.

... Additionally, BPC 157 has shown promise in treating gastrointestinal disorders and reducing gastric and colon cancer risk (Sikiric et al., 2021). Its role in facilitating improved recoverability of soft tissue structures (Pevec et al., 2010;Chang et al., 2011;Gwyer et al., 2019) and streamlined neurocognitive performance (Sikiric et al., 2023;Vukojević et al., 2022) are of particular interest among the general population and thus will serve as the focus of this review. ...

Joseph Anthony Giandonato Victor Tringali

p>Interest in Pentadecapeptide BPC 157, an oligopeptide originally derived from human gastric juice, has grown substantially among members of the fitness community in the past few years due to its wide range of purported and previously reported effects on improving health and enhancing performance. In spite of these effects, the use of BPC 157 is accompanied by uncertainties, specifically the impact of long-term use. The composition, pharmacokinetics, route of administration and potential clinical applications will be presented in this brief investigative report. Article visualizations: </p

... One unusual drug showed important benefits in an SCI rat model: the stable gastric pentadecapeptide BPC 157. The beneficial effects of the stable gastric pentadecapeptide BPC 157 have been reported in several organ systems, and recently in CNS disorders, including rat models of stroke and hippocampal ischemia/reperfusion injury, catalepsy and schizophrenia, and spinal cord injury ( 161 ). In a rat model of spinal cord compression, the application of BPC 157 showed advanced healing and functional recovery (counteracted tail paralysis). ...

Israel Grijalva

Ernesto Doncel-Pérez

Barbara Zofia Pietrzyk

Maciej Waluga

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

Predrag Sikiric

Sven Seiwerth

Anita Skrtic 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.

Hrvoje Mazija

Zlatko Janjecic

Dalibor Bedeković

Predrag Sikiric

Sažetak Istražen je učinak pentadekapeptida BPC 157 na tovnost muških tovnih pilića. Po prvi puta in vivo primijenjen je jednokratno netom izleženim pilićima i to postupkom nebulizacije ultrazvučnim raspršivaćem SONOVAC ® , aerosolom veličine čestica 3-5 mikrona. Svako je pile udahnulo približno količinu 7,5 μg BPC 157 tijekom 60 odnosno upola manje tijekom 30 sekundi. Učinak se je u oba slučaja očitovao značajno bržim prirastom tjelesne mase u odnosu na kontrolnu skupinu kojoj je istim postupkom dana fiziološka otopina PBS. Nakon 35 dana tova pilići skupine kojoj je BPC 157 primijenjen tijekom 30 sekundi bili su najteži (2297,0 g) uz istodobno najmanji utrošak krmne smjese za ostvareni prirast (1,64 kg/kg). Najveću tjelesnu masu postigli su pilići u dobi 42 dana (3032,28 g) ali uz veći utrošak krme u odnosu na kontrolnu skupinu (1,73 prema 1,54 kg/kg). BPC 157 primijenjen je po prvi puta netom izleženim muškim pilićima uz postizanje veće tjelesne mase u odnosu na kontrolnu skupinu. Također dokazano je da je učinak BPC 157 ovisan o primijenjnoj količini. Postignute rezultate treba prihvatiti kao osnovu za nastavak istraživanja. Abstract The effect of pentadecapeptide BPC 157 on male fattening chickens was investigated. For the first time in vivo it was administered once to a net hatched chicken by an ultrasonic spray nebulization process SONOVAC®, a particle size aerosol of 3-5 microns. Each saw inhaled approximately 7.5 μg of BPC 157 over 60 and half less over 30 seconds, respectively. The effect in both cases manifested a significantly faster body mass control in relation to the same saline. After 35 days of fattening, the chickens of the group to which BPC 157 was applied for 30 seconds were the heaviest (2297, g) at the same time the lowest consumption of compound feed for increment (1.64 kg/kg). The largest body weight was achieved by chickens aged 42 days (3032.28 g) but with a higher feed consumption. BPC 157 was administered for the first time to net hatched male chickens with a higher body weight compared to the control group. It has also been proven that the effect of BPC 157 depends on the amount applied. The results achieved should be accepted as a basis for continuing the research.

Ming-Jer Hsieh

Cheng-Hung Lee Ho-Yen Chueh

Jong-Hwei Pang

BPC 157-activated endothelial nitric oxide synthase (eNOS) is associated with tissue repair and angiogenesis as reported in previous studies. However, how BPC 157 regulates the vasomotor tone and intracellular Src-Caveolin-1 (Cav-1)-eNOS signaling is not yet clear. The present study demonstrated a concentration-dependent vasodilation effect of BPC 157 in isolated rat aorta. Attenuation of this vasodilation effect in the absence of endothelium suggested an endothelium-dependent vasodilation effect of BPC 157. Although slightly increased vasorelaxation in aorta without endothelium was noticed at high concentration of BPC 157, there was no direct relaxation effect on three-dimensional model made of vascular smooth muscle cells. The vasodilation effect of BPC 157 was nitric oxide mediated because the addition of L-NAME or hemoglobin inhibited the vasodilation of aorta. Nitric oxide generation was induced by BPC 157 as detected by intracellular DFA-FM DA labeling which was capable of promoting the migration of vascular endothelial cells. BPC 157 enhanced the phosphorylation of Src, Cav-1 and eNOS which was abolished by pretreatment with Src inhibitor, confirming the upstream role of Src in this signal pathway. Activation of eNOS required the released binding with Cav-1 in advance. Co-immunoprecipitation analysis revealed that BPC 157 could reduce the binding between Cav-1 and eNOS. Together, the present study demonstrates that BPC 157 can modulate the vasomotor tone of an isolated aorta in a concentration- and nitric oxide-dependent manner. BPC 157 can induce nitric oxide generation likely through the activation of Src-Cav-1-eNOS pathway.

Jaksa Vukojevic

Borna Vrdoljak

Dominik Malekinusic

Predrag Sikiric

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

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.

Marijan Kolovrat

Slaven Gojkovic

Ivan Krezic

Predrag Sikiric

Background: The Pringle maneuver [portal triad obstruction(PTO)] provides huge disturbances during ischemia and even more thereafter in reperfusion. Contrarily, a possible solution may be stable gastric pentadecapeptide BPC 157, with already documented beneficial effects in ischemia/reperfusion conditions. Recently, BPC 157, as a cytoprotective agent, successfully resolved vessel occlusions in rats (ischemic colitis; deep vein thrombosis, superior anterior pancreaticoduodenal vein; bile duct cirrhosis) through rapid collateral vessel recruitment to circumvent vessel occlusion. Thereby, medication BPC 157 regimens were administered as a single challenge before and during ischemia or, alternatively, at various time points during reperfusion. Aim: To introduce BPC 157 therapy against pringle maneuver-damage. Methods: In deeply anesthetised rats, the portal triad was clamped up for 30 min. Rats then underwent reperfusion for either 15 min or 24 h. Medication [(10 μg, 10 ng/kg) regimens, administered as a single challenge] picked (a) ischemia, PTO period [at 5 min before (ip) or at 5 or 30 min of ligation time (as a bath to PTO)] or (b) reperfusion, post-PTO period [at 1 or 15 min (bath during surgery) or 24 h (ip) reperfusion-time]. We provided gross, microscopy, malondialdehyde, serum enzymes, electrocardiogram, portal, caval, and aortal pressure, thrombosis and venography assessments. Results: BPC 157 counteracts electrocardiogram disturbances (increased P wave amplitude, S1Q3T3 QRS pattern and tachycardia). Rapidly presented vascular pathway (portal vein-superior mesenteric vein-inferior mesenteric vein-rectal veins-left ileal vein-inferior caval vein) as the adequate shunting immediately affected disturbed haemodynamics. Portal hypertension and severe aortal hypotension during PTO, as well as portal and caval hypertension and mild aortal hypotension in reperfusion and refractory ascites formation were markedly attenuated (during PTO) or completely abrogated (reperfusion); thrombosis in portal vein tributaries and inferior caval vein or hepatic artery was counteracted during portal triad obstruction PTO. Also, counteraction included the whole vicious injurious circle [i.e., lung pathology (severe capillary congestion), liver (dilated central veins and terminal portal venules), intestine (substantial capillary congestion, submucosal oedema, loss of villous architecture), splenomegaly, right heart (picked P wave values)] regularly perpetuated in ischemia and progressed by reperfusion in Pringle rats. Conclusion: BPC 157 resolves pringle maneuver-damage in rats, both for ischemia and reperfusion.

Slaven Gojkovic

Ivan Krezic

Borna Vrdoljak

Predrag Sikiric

Background: Recently, as a possible therapy resolving solution, pentadecapeptide BPC 157 therapy, has been used in alleviating various vascular occlusion disturbances. BPC 157 was previously reviewed as novel mediator of Robert cytoprotection and endothelium protection in the stomach, and gut-brain axis, beneficial therapy in gastrointestinal tract, with particular reference to vascular recruitment, ulcerative colitis and tumor cachexia, and other tissues healing. Here we raised new hypothesis about BPC 157 therapy in the Budd-Chiari syndrome in rats, rapid bypassing of the suprahepatic inferior caval vein occlusion, and rats recovery with the active and effective pharmacotherapy treatment. Aim: To investigate Budd-Chiari syndrome model (inferior caval vein suprahepatic occlusion) resolution, since BPC 157 resolves various rat vascular occlusion. Methods: We assessed the activated bypassing pathways between the inferior and superior caval veins and portocaval shunt, counteracted caval/portal hypertension, aortal hypotension, venous/arterial thrombosis, electrocardiogram disturbances, liver and gastrointestinal lesions (i.e., stomach and duodenum hemorrhages, in particular, congestion). Rats with suprahepatic occlusion of the inferior vena cava by ligation were medicated at 1 min, 15 min, 24 h, or 48 h post-ligation. Medication consisted of 10 μg/kg BPC 157, 10 ng BPC 157 or 5 mL/kg saline, administered once as an abdominal bath or intragastric application. Gross and microscopic observations were made, in addition to assessments of electrical activity of the heart (electrocardiogram), portal and caval hypertension, aortal hypotension, thrombosis, hepatomegaly, splenomegaly and venography. Furthermore, levels of nitric oxide, malondialdehyde in the liver and serum enzymes were determined. Results: BPC 157 counteracted increased P wave amplitude, tachycardia and ST-elevation, i.e., right heart failure from acute thrombotic coronary occlusion. The bypassing pathway of the inferior vena cava-azygos (hemiazygos) vein-superior vena cava and portocaval shunt occurred rapidly. Even with severe caval ˃ portal hypertension, BPC 157 antagonized portal and caval hypertension and aortal hypotension, and also reduced refractory ascites. Thrombosis of portal vein tributaries, inferior vena cava, and hepatic and coronary arteries was attenuated. In addition, there was reduced pathology of the lungs (severe capillary congestion) and liver (dilated central veins and terminal portal venules), decreased intestine hemorrhagic lesions (substantial capillary congestion, submucosal edema and architecture loss), and increased liver and spleen weight. During the period of ligation, nitric oxide- and malondialdehyde-levels in the liver remained within normal healthy values, and increases in serum enzymes were markedly reduced. Conclusion: BPC 157 counteracts Budd Chiari syndrome in rats.

Sanja Konosic

Mate Petricevic

višnja ivančan

Predrag Sikiric

We suggest that the stable gastric pentadecapeptide BPC 157 may rescue thrombocyte function. We focused on the antithrombotic agent aspirin, clopidogrel, and cilostazol application in rats; arachidonic acid, ADP, collagen, and arachidonic acid/PGE1 platelet aggregation (aggregometry) and blood clot viscoelastic properties (thromboelastometry); and the pentadecapeptide BPC 157. Rats received intragastrically for three days once daily treatment with antithrombotic agents—aspirin (10 mg/kg) or clopidogrel (10 mg/kg) or cilostazol (10 mg/kg). Medication (BPC 157 (10 μ g/kg) or an equal volume of saline (5 ml/kg)) was given intragastrically, immediately after each antithrombotic agent application. For multiple electrode aggregometry and modified rotational thromboelastometry studies, blood sampling was at 2 h after last application. Adenosine diphosphate (ADP test 6.5 μ M), arachidonic acid (ASPI test 0.5 mM), a combination of arachidonic acid and prostaglandin E1 (ASPI test 0.5 mM and PGE1-test 30 nM), and collagen (COL test 3.2 μ g/ml) were used as aggregation agonists. Given with aspirin, clopidogrel, or cilostazol in rats, BPC 157 counteracted their inhibitory effects on aggregation activated by arachidonic acid, ADP, collagen, and arachidonic acid/PGE1. Specifically, this includes recovery of the aggregation induced by arachidonic acid ( vs. aspirin, vs. clopidogrel, and vs. cilostazol), arachidonic acid/PGE1 ( vs. cilostazol), ADP ( vs. clopidogrel), or collagen ( vs. clopidogrel). Contrarily, there is no effect on the used tests (extrinsic/intrinsic hemostasis system, the fibrin part of the clot) EXTEM, INTEM, and FIBTEM; clotting time; clot formation time; alpha-angle; maximum clot firmness; lysis index after 30 minutes; and maximum lysis. In conclusion, we revealed that BPC 157 largely rescues thrombocyte function.

Darko Perovic

Danijela Kolenc Vide Bilic

Predrag Sikiric

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

Andrea Zemba Čilić

Mladen Zemba Matija Cilic

Predrag Sikiric

In the suited rat-models, we focused on the stable pentadecapeptide BPC 157, L-NAME, NOS-inhibitor, and L-arginine, NOS-substrate, relation, the effect on schizophrenia-like symptoms. Medication (mg/kg intraperitoneally) was L-NAME (5), L-arginine (100), BPC 157 (0.01), given alone and/or together, at 5 min before the challenge for the acutely disturbed motor activity (dopamine-indirect/direct agonists (amphetamine (3.0), apomorphine (2.5)), NMDA-receptor non-competitive antagonist (MK-801 (0.2)), or catalepsy, (dopamine-receptor antagonist haloperidol (2.0)). Alternatively, BPC 157 10 μg/kg was given immediately after L-NAME 40 mg/kg intraperitoneally. To induce or prevent sensitization, we used chronic methamphetamine administration, alternating 3 days during the first 3 weeks, and challenge after next 4 weeks, and described medication (L-NAME, L-arginine, BPC 157) at 5 min before the methamphetamine at the second and third week. Given alone, BPC 157 or L-arginine counteracted the amphetamine-, apomorphine-, and MK-801-induced effect, haloperidol-induced catalepsy and chronic methamphetamine-induced sensitization. L-NAME did not affect the apomorphine-, and MK-801-induced effects, haloperidol-induced catalepsy and chronic methamphetamine-induced sensitization, but counteracted the acute amphetamine-induced effect. In combinations (L-NAME + L-arginine), as NO-specific counteraction, L-NAME counteracts L-arginine-induced counteractions in the apomorphine-, MK-801-, haloperidol- and methamphetamine-rats, but not in amphetamine-rats. Unlike L-arginine, BPC 157 maintains its counteracting effect in the presence of the NOS-blockade (L-NAME + BPC 157) or NO-system-over-stimulation (L-arginine + BPC 157). Illustrating the BPC 157-L-arginine relationships, BPC 157 restored the antagonization (L-NAME + L-arginine + BPC 157) when it had been abolished by the co-administration of L-NAME with L-arginine (L-NAME + L-arginine). Finally, BPC 157 directly inhibits the L-NAME high dose-induced catalepsy. Further studies would determine precise BPC 157/dopamine/glutamate/NO-system relationships and clinical application.

Jong Min Park Ho Jae Lee

Predrag Sikiric Ki Baik Hahm

The stable gastric pentadecapeptideBPC 157 protects stomach cells, maintains gastric integrity against various noxious agents such as alcohol, nonsteroidal anti-inflammatory drugs (NSAIDs), and exerts cytoprotection/adaptive cytoprotection/organoprotection in other epithelia, that is, skin, liver, pancreas, heart, and brain. Especially 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 including thrombosis, prolonged bleeding, and thrombocytopenia. In this background, we put the importance of BPC 157 as possible way of securing GI safety against NSAIDsinduced gastroenteropathy since still unmet medical needs to mitigate NSAIDs-induced cytotoxicity are urgent. Furthermore, gastrointestinal irritants such as physical or mental stress, NSAIDs administration, surfactants destroyer such as bile acids, alcohol can lead to leaky gut syndromethrough increasingepithelial permeability. In this review article, we described the potential rescuing actions of BPC 157 against leaky gut syndrome after NSAIDs administration for the first time.

Predrag Sikiric Domagoj Drmic Marko Sever

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.