BPC-157 (10mg)

Research Overview

BPC-157 is a synthetic pentadecapeptide examined in cell-free assays, cultured cell systems and animal research models. The mechanistic literature converges on a few signalling routes, taken in turn below.

One finding frames the rest. In cultured cells alone, BPC-157 produced no direct angiogenic effect, while in crushed and transected muscle and tendon research models the same work recorded modulated angiogenesis with upregulated vascular endothelial growth factor (VEGF) expression, assessed by VEGF, CD34 and FVIII immunohistochemistry [1].

Angiogenic Signaling and VEGFR2

In vascular endothelial cell culture, BPC-157 was associated with increased mRNA and protein expression of vascular endothelial growth factor receptor 2 (VEGFR2), with no matching change in VEGF-A itself [2].

The same work reported increased VEGFR2 internalization and time-dependent activation of the VEGFR2-Akt-eNOS pathway. Both the internalization and the increase in endothelial tube formation were abolished by dynasore, an endocytosis inhibitor, which places receptor internalization upstream of the signalling [2].

Nitric Oxide Generation and Vascular Tone

In isolated rat aorta, BPC-157 produced concentration-dependent vasodilation that was attenuated when the endothelium was absent and abolished by L-NAME or hemoglobin, indicating a nitric oxide mediated and endothelium-dependent route [3].

Nitric oxide generation was detected directly by intracellular labelling, and BPC-157 increased phosphorylation of Src, Caveolin-1 and eNOS. Adding a Src inhibitor beforehand abolished that cascade, and co-immunoprecipitation showed reduced binding between Caveolin-1 and eNOS, which is the step that frees eNOS to act [3].

A separate study used blockade of nitric oxide synthase by retrobulbar L-NAME in rats. Fundoscopy and histology recorded vessel calibre irregularity and changes in the inner plexiform and inner nuclear layers, while co-applied BPC-157 was associated with normal retinal thickness at one, two and four weeks [4].

Endothelial Proliferation and ERK1/2 Signaling

In HUVEC culture, BPC-157 was associated with increased proliferation on MTT and cell cycle analysis, and with increased migration on both transwell and scratch assays [5].

The same work recorded upregulated VEGF-a expression, accelerated vascular tube formation in vitro, and increased phosphorylation of ERK1/2 along with its downstream targets c-Fos, c-Jun and Egr-1 [5].

Early Growth Response Gene Expression and Matrix Organization

The same fifteen-residue sequence, studied under the designation PL 14736, stimulated expression of the immediate response gene egr-1 and its repressor nab2 in non-differentiated Caco-2 cells, and did so more rapidly than PDGF-BB in the same comparison [6].

In a sponge implantation granulation model the sequence was more active than PDGF-BB in early collagen organization, which the authors link to EGR-1 driven extracellular matrix formation [6].

Growth Factor Receptor Expression in Tendon Fibroblasts

cDNA microarray analysis of rat Achilles tendon fibroblasts identified growth hormone receptor as one of the most abundantly upregulated genes under BPC-157 [7].

Expression rose with concentration and time at both mRNA and protein level, by real-time PCR and Western blot. Adding growth hormone to BPC-157 exposed fibroblasts increased proliferation and PCNA expression, and Janus kinase 2, the downstream signal of that receptor, was activated time-dependently [7].

Fibroblast Migration and Adhesion Signaling

In tendon explant culture, BPC-157 accelerated fibroblast outgrowth, while MTT assay showed no direct effect on proliferation of already-cultured fibroblasts. Survival under hydrogen peroxide stress increased, as did migration on transwell assay and spreading on culture dishes [8].

F-actin formation was induced, and phosphorylation of FAK and paxillin increased with concentration while total protein amounts stayed unchanged, which points to the FAK-paxillin route rather than to a change in protein abundance [8].

Earlier work in cultured tendocytes found no effect of BPC-157 on cell growth on its own, but it opposed 4-hydroxynonenal, a negative modulator of growth, reversing that inhibition into stimulation in both serum and serum-deprived conditions [9].

Connective and Mineralized Tissue Research Models

In rats with the quadriceps transected transversely, BPC-157 was associated with increased load of failure, desmin positivity indicating ongoing muscle fibre regeneration, and larger myofibril diameters on both sides of the cut over 72 days [10].

In a myotendinous junction defect model, assessments covered biomechanical and functional measures alongside mRNA levels, oxidative stress and nitric oxide levels at the junction, with BPC-157 counteracting the changes recorded in controls [11].

In rabbit radius segmental defects, radiographic callus surface, microphotodensitometry and quantitative histomorphometry recorded improved bone continuity across the defect, at a level comparable to local bone marrow application or an autologous cortical graft [12].

Epithelial Surface Research Models

A 2 mm penetrant linear corneal incision in rats was used to follow epithelial closure. Under BPC-157 eye drops, fluorescein and Seidel tests turned negative and the epithelial defects closed at 72 hours at the higher concentration and 96 hours at the lower one [13].

Vessel ingrowth differed too. Controls developed new vessels growing from the limbus to the penetrated area, while in the BPC-157 group vessels either did not form or did not reach it [13].

All of these endpoints are measured under controlled laboratory conditions. BPC-157 is characterized in that setting for angiogenic signalling, nitric oxide pathway activity, growth factor receptor expression, adhesion signalling and tissue-repair research models.

References

1. Brcic L, Brcic I, Staresinic M, Novinscak T, Sikiric P, Seiwerth S. (2009). Modulatory effect of gastric pentadecapeptide BPC 157 on angiogenesis in muscle and tendon healing. Journal of Physiology and Pharmacology. PMID 20388964
2. Hsieh MJ, Liu HT, Wang CN, Huang HY, Lin Y, Ko YS, Wang JS, Chang VH, Pang JS. (2017). Therapeutic potential of pro-angiogenic BPC157 is associated with VEGFR2 activation and up-regulation. Journal of Molecular Medicine. https://doi.org/10.1007/s00109-016-1488-y
3. Hsieh MJ, Lee CH, Chueh HY, Chang GJ, Huang HY, Lin Y, Pang JS. (2020). Modulatory effects of BPC 157 on vasomotor tone and the activation of Src-Caveolin-1-endothelial nitric oxide synthase pathway. Scientific Reports. https://doi.org/10.1038/s41598-020-74022-y
4. Zlatar M, Kokot A, Batelja Vuletic L, Masnec S, Kralj T, Milkovic Perisa M, Barisic I, Radic B, Milanovic K, Drmic D, Seiwerth S, Sikiric P. (2021). BPC 157 as a Therapy for Retinal Ischemia Induced by Retrobulbar Application of L-NAME in Rats. Frontiers in Pharmacology. https://doi.org/10.3389/fphar.2021.632295
5. Huang T, Zhang K, Sun L, Xue X, Zhang C, Shu Z, Mu N, Gu J, Zhang W, Wang Y, Zhang Y, Zhang W. (2015). Body protective compound-157 enhances alkali-burn wound healing in vivo and promotes proliferation, migration, and angiogenesis in vitro. Drug Design, Development and Therapy. https://doi.org/10.2147/DDDT.S82030
6. Tkalcevic VI, Cuzic S, Brajsa K, Mildner B, Bokulic A, Situm K, Perovic D, Glojnaric I, Parnham MJ. (2007). Enhancement by PL 14736 of granulation and collagen organization in healing wounds and the potential role of egr-1 expression. European Journal of Pharmacology. https://doi.org/10.1016/j.ejphar.2007.05.072
7. Chang CH, Tsai WC, Hsu YH, Pang JH. (2014). Pentadecapeptide BPC 157 Enhances the Growth Hormone Receptor Expression in Tendon Fibroblasts. Molecules. https://doi.org/10.3390/molecules191119066
8. Chang CH, Tsai WC, Lin MS, Hsu YH, Pang JH. (2011). The promoting effect of pentadecapeptide BPC 157 on tendon healing involves tendon outgrowth, cell survival, and cell migration. Journal of Applied Physiology. https://doi.org/10.1152/japplphysiol.00945.2010
9. Staresinic M, Sebecic B, Patrlj L, Jadrijevic S, Suknaic S, Perovic D, Aralica G, Zarkovic N, Borovic S, Srdjak M, Hajdarevic K, Kopljar M, Batelja L, Boban-Blagaic A, Turcic I, Anic T, Seiwerth S, Sikiric P. (2003). Gastric pentadecapeptide BPC 157 accelerates healing of transected rat Achilles tendon and in vitro stimulates tendocytes growth. Journal of Orthopaedic Research. https://doi.org/10.1016/S0736-0266(03)00110-4
10. Staresinic M, Petrovic I, Novinscak T, Jukic I, Pevec D, Suknaic S, Kokic N, Batelja L, Brcic L, Boban-Blagaic A, Zoric Z, Ivanovic D, Ajduk M, Sebecic B, Patrlj L, Sosa T, Buljat G, Anic T, Seiwerth S, Sikiric P. (2006). Effective therapy of transected quadriceps muscle in rat. Gastric pentadecapeptide BPC 157. Journal of Orthopaedic Research. https://doi.org/10.1002/jor.20089
11. Japjec M, Horvat Pavlov K, Petrovic A, Staresinic M, Sebecic B, Buljan M, Vranes H, Giljanovic A, Drmic D, Japjec M, Prtoric A, Lovric E, Batelja Vuletic L, Dobric I, Boban Blagaic A, Skrtic A, Seiwerth S, Sikiric P. (2021). Stable Gastric Pentadecapeptide BPC 157 as a Therapy for the Disable Myotendinous Junctions in Rats. Biomedicines. https://doi.org/10.3390/biomedicines9111547
12. Sebecic B, Nikolic V, Sikiric P, Seiwerth S, Sosa T, Patrlj L, Grabarevic Z, Rucman R, Petek M, Konjevoda P, Jadrijevic S, Perovic D, Slaj M. (1999). Osteogenic effect of a gastric pentadecapeptide, BPC-157, on the healing of segmental bone defect in rabbits. Bone. https://doi.org/10.1016/s8756-3282(98)00180-x
13. Masnec S, Kokot A, Zlatar M, Kalauz M, Kunjko K, Radic B, Klicek R, Drmic D, Lazic R, Brcic L, Radic R, Ivekovic R, Seiwerth S, Sikiric P. (2015). Perforating corneal injury in rat and pentadecapeptide BPC 157. Experimental Eye Research. https://doi.org/10.1016/j.exer.2015.04.016