BPC-157 Potential On Angiogenesis and Cell Survival

BPC-157, often described as a stable gastric pentadecapeptide (preliminary observations indicate that it may withstand degradation within gastric environments), is a synthetic peptide made of 15 amino acids.⁽¹⁾ It is also sometimes identified under the designations L 14736, PL-10, and Bepecin. Experimental work suggests that it might influence signaling cascades possibly related to wound healing, including the formation of new blood vessels and modulation of inflammatory responses. Some data imply that it might aid in regenerating various tissues, such as dermal tissue or muscular tissue. Attempts to understand its exact mechanism have led to speculation that it may counteract adverse processes like tissue necrosis or impaired angiogenesis.

Figure 1: BPC-157 chemical structure

 

Research

BPC-157 Potential On Angiogenesis

BPC-157 is posited to support cellular survival and regeneration primarily by modifying angiogenesis. There are several potential pathways for the peptide to do so:

• BPC-157 may modify one of the major classes of receptors that stimulate angiogenesis, namely the Vascular Endothelial Growth Factor Receptor 2 (VEGFR2). Research by Hsieh et al. suggests that BPC-157 may up-regulate the expression of VEGFR2 in endothelial cells, as indicated by observed increases in both VEGFR2 mRNA and protein levels in cultured endothelial cells. ⁽²⁾ This up-regulation might facilitate a more robust VEGF-A and VEGFR2 interaction, which is crucial for angiogenesis. Additionally, BPC-157 appears to promote the internalization of VEGFR2, a process that is typically associated with VEGFR2 activation. The internalization of VEGFR2 by BPC-157 may lead to the activation of downstream signaling pathways, specifically the VEGFR2-Akt-eNOS cascade. Activation of this pathway is potentially significant for angiogenesis, as it may support endothelial cell survival, proliferation, and the formation of new blood vessels.
• By activating the eNOS enzyme, the peptide appears to upregulate NO synthesis, which is a major vasodilator fundamentally involved in vascular function and angiogenesis. Moreover, the peptide appears to modulate the NO pathway, which is fundamentally involved in vascular function and angiogenesis. Specifically, BPC-157 may interact with endothelial cells, providing endothelium protection by possibly maintaining NO bioavailability. This interaction might facilitate the stabilization of blood vessels and support new blood vessel formation, a process essential for angiogenesis. Sikiric et al. have commended that the peptide may counteract the actions of NO synthase (NOS) inhibitors like L-NAME, which suggests that BPC-157 might help sustain NO production under conditions where it is otherwise diminished. ⁽³⁾ This maintenance of NO levels might prove critical in ensuring adequate blood flow and vessel integrity during the angiogenic process.
• Furthermore, BPC-157 is believed to influence the expression of the early growth response 1 (egr-1) gene, which is responsible for the generation of cytokines and growth factors that are pivotal in the angiogenic process.⁽³⁾ Researchers such as Tkalcević et al. suggest that by stimulating egr-1, BPC-157 may support the production of factors that promote endothelial cell proliferation and migration, thereby potentially fostering the formation of new blood vessels. ⁽⁴⁾ Furthermore, the researchers posited that the activation of “EGR-1 induces cytokine and growth factor generation and early extracellular matrix (collagen) formation,” which further elucidates the mechanisms behind the regenerative potential of BPC-157.

BPC-157 Potential On Digestive System Tissues

A study by Luetic et al. suggests that by supporting angiogenesis, BPC-157 may support the recovery and regeneration of digestive system tissues in laboratory conditions.⁽⁵⁾ Specifically, BPC-157 may aid in restoring vascular integrity and promoting tissue repair. In addition, BPC-157 appears to potentially mitigate the elevated levels of malondialdehyde (MDA) during experimentally induced oxidative stress. Elevated MDA is posited to be a marker of oxidative stress, which may lead to cellular damage and impede tissue recovery. By possibly attenuating oxidative stress markers, BPC-157 may help protect gastric and duodenal cells from reactive oxygen species (ROS)-induced cytotoxicity.

Additionally, another study by Sikiric et al. suggests that BPC-157 may also interact with adrenergic and dopaminergic receptors to exert its gastroprotective potential.⁽⁶⁾ The peptide’s protective action was reportedly abolished by agents targeting alpha-adrenergic receptors (such as phentolamine and clonidine) and dopaminergic receptors (such as haloperidol), suggesting a potential involvement of these pathways. Furthermore, the protective action was influenced by beta-adrenergic blockers like atenolol and propranolol, depending on the route of BPC-157 administration. This indicates that BPC-157 might modulate catecholamine release and dopamine receptor activity, contributing to its ability to protect against gastrointestinal lesions under stress conditions.

BPC-157 Potential On Neuron Survival

BPC-157 may exhibit neuroprotective actions on nerve cells. Research by Tohyama et al. suggests it might protect peripheral sensory neurons, which are cells responsible for transmitting information like touch and pain to the spinal cord, and potentially promote the regrowth of peripheral nerves following injury. ⁽⁷⁾ This may include reducing the death of nerve cells, limiting the degradation of the myelin sheath (a lipid-rich layer insulating nerve fibers), and mitigating the formation of cysts (fluid-filled cavities) in the affected nerve tissue. This potential may be based on the ability of BPC-157 to modify the expression of egr-1 and its co-repressor NAB2 (NGFI-A-binding protein-2), which are transcription factors that may influence gene expression patterns during neuronal growth, differentiation, or injury responses.

By interacting with NAB2, studies by Sikiric et al. also suggest that BPC-157 might affect inflammatory responses, thereby modulating inflammation or tissue remodeling.⁽³⁾ Reductions in harmful inflammatory factors may, in turn, favor neuronal stability and potentially assist in repairing nerve damage. Alterations in gene expression influenced by Egr-1 and NAB2 may also, in uncertain ways, control the production of proteins needed for neuronal growth and differentiation, potentially offering some level of indirect support against injury. Furthermore, studies suggest that by engaging multiple neurotransmitter and signaling systems, including the interplay between serotonergic and dopaminergic pathways, and by potentially influencing GABAergic inhibition, opioid-related analgesia, and inflammatory processes, BPC-157 may ultimately shape a neurochemical environment that encourages neuron survival and nerve tissue regeneration. However, its overall impact remains far from fully understood.

BPC-157 Potential On Connective Tissue Cells

Research by Chang et al. suggests that BPC-157 may influence connective tissue cells and facilitate connective tissue recovery. According to the researchers, BPC-157 appears to possibly support the outgrowth of tendon fibroblasts from tendon explants in laboratory settings, which may indicate a role in promoting the initial stages of tendon regeneration. This peptide may also potentially increase the survival of tendon fibroblasts under oxidative stress conditions, suggesting a protective action that might support cell viability during the healing process. Furthermore, BPC-157 is posited to support the migratory capacity of tendon fibroblasts.

The scientists involved in these studies commented that “BPC 157 markedly increased the in vitro migration of tendon fibroblasts […] as revealed by transwell filter migration assay.”  This increased cell migration may be crucial for repopulating the injured tissue model with necessary cellular components. Additionally, BPC-157 may accelerate the spreading of tendon fibroblasts on culture surfaces, which is an essential aspect of cell adhesion and movement within the extracellular matrix.

At the molecular level, the peptide is thought to possibly induce the formation of F-actin, a key component of the cytoskeleton involved in cell movement and structural integrity. This induction of F-actin formation is believed to facilitate better-supported migration and spreading and possibly have a role in activating tendon fibroblasts exposed to BPC-157. Moreover, BPC-157 is suggested to activate the FAK-paxillin signaling pathway. The phosphorylation of FAK and paxillin, which are integral to focal adhesion dynamics and cell motility, might underlie the increased migratory behavior of tendon fibroblasts. This activation may potentially lead to the strengthening of intracellular signaling networks that govern cell movement and interaction with the extracellular matrix. Furthermore, BPC-157 seemed to increase cell survival under oxidative stress induced by hydrogen peroxide (H₂O₂).

 
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References:

1. Seiwerth S, Milavic M, Vukojevic J, Gojkovic S, Krezic I, Vuletic LB, Pavlov KH, Petrovic A, Sikiric S, Vranes H, Prtoric A, Zizek H, Durasin T, Dobric I, Staresinic M, Strbe S, Knezevic M, Sola M, Kokot A, Sever M, Lovric E, Skrtic A, Blagaic AB, Sikiric P. Stable Gastric Pentadecapeptide BPC 157 and Wound Healing. Front Pharmacol. 2021 Jun 29;12:627533. doi: 10.3389/fphar.2021.627533. PMID: 34267654; PMCID: PMC8275860.
2. Hsieh MJ, Liu HT, Wang CN, Huang HY, Lin Y, Ko YS, Wang JS, Chang VH, Pang JS. The therapeutic potential of pro-angiogenic BPC157 is associated with VEGFR2 activation and up-regulation. J Mol Med (Berl). 2017 Mar;95(3):323-333. doi: 10.1007/s00109-016-1488-y. Epub 2016 Nov 15. PMID: 27847966.
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4. Tkalcević VI, Cuzić S, Brajsa K, Mildner B, Bokulić A, Situm K, Perović D, Glojnarić I, Parnham MJ. Enhancement by PL 14736 of granulation and collagen organization in healing wounds and the potential role of egr-1 expression. Eur J Pharmacol. 2007 Sep 10;570(1-3):212-21. doi: 10.1016/j.ejphar.2007.05.072. Epub 2007 Jun 16. PMID: 17628536.
5. Luetic K, Sucic M, Vlainic J, Halle ZB, Strinic D, Vidovic T, Luetic F, Marusic M, Gulic S, Pavelic TT, Kokot A, Seiwerth RS, Drmic D, Batelja L, Seiwerth S, Sikiric P. Cyclophosphamide induced stomach and duodenal lesions as a NO-system disturbance in rats: L-NAME, L-arginine, stable gastric pentadecapeptide BPC 157. Inflammopharmacology. 2017 Apr;25(2):255-264. doi: 10.1007/s10787-017-0330-7. Epub 2017 Mar 2. PMID: 28255738.
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7. Tohyama Y, Sikirić P, Diksic M. Effects of pentadecapeptide BPC157 on regional serotonin synthesis in the rat brain: alpha-methyl-L-tryptophan autoradiographic measurements. Life Sci. 2004 Dec 3;76(3):345-57. doi: 10.1016/j.lfs.2004.08.010. PMID: 15531385.
8. Chang CH, Tsai WC, Lin MS, Hsu YH, Pang JH. The promoting effect of pentadecapeptide BPC 157 on tendon healing involves tendon outgrowth, cell survival, and cell migration. J Appl Physiol (1985). 2011 Mar;110(3):774-80. doi: 10.1152/japplphysiol.00945.2010. Epub 2010 Oct 28. PMID: 21030672.