Stable Gastric Pentadecapeptide BPC 157 as a Therapy and Safety Key: A Special Beneficial Pleiotropic Effect Controlling and Modulating Angiogenesis and the NO-System

Abstract

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.

Keywords: BPC 157; angiogenesis; control/modulation; nitric oxide.

Figure 1

Illustrative distinctive presentation of control (small letters) and BPC 157-treated rats (capital letters). Summary of the effects of controlled angiogenesis, opposed angiogenesis (cornea) [76], advanced angiogenesis (tendon, muscle) [88,89] (BPC 157 therapy) (A–D) vs. regularly failed angiogenesis (control), (e–h) corneal neovascularization, failed healing tendon and muscle. BPC 157 therapy. (A,B) Corneal ulcer (60× magnification). BPC 157 2 pg/mL, 2 ng/mL, and 2 µg/mL distilled water, two eye drops/left rat eye immediately after injury induction, and then every 8 h up to 120 h. (A) Absence of edema in the site of ulceration, new vessels markedly attenuated, corneal transparency, no signs of inflammatory process, on post-operative day 3. (B) On post-operative day 5, staining the cornea with fluorescein dye and examination under blue light shows a negative fluorescein test, epithelial defect at the site of ulceration healed, and the defect does not persist. The cornea is flat, and there are no abnormalities. (C,D) Gross presentation after the rat’s Achilles tendon was sharply transected from the calcaneal bone (C) and after major muscle transection (quadriceps muscle) (D) (yellow arrow). BPC 157 regimens 10 µg, 10 ng, 10 pg/kg, intraperitoneally, once daily. (C) Detached tendon, no defect between the tendon stump and the calcaneal bone at post-operative day 10. The edge of the tendon stump cannot be recognized (osteotendon junction re-established). (D) Improved gross presentation of transected muscle, muscle presentation with regeneration and absent marked atrophy, at day post-surgery day 72, and there was always functional, biomechanical, microscopical, and immunohistochemistry healing improvement. Controls. (e,f) Corneal ulcer (60× magnification). (e) Edema at the site of ulceration, growth of new vessels, corneal opacity, and poor transparency on post-operative day 3. The inflammatory process is active. (f) At postoperative day 5, staining the cornea with fluorescein dye and examination under blue light shows a positive fluorescein test, epithelial defects (green areas) at the site of ulceration, the surface of the cornea is not flat, and defects and inflammatory conditions still persist. (g,h) (red arrow) Gross presentation after the rat’s Achilles tendon was sharply transected from the calcaneal bone (g) and after major muscle transection (quadriceps muscle) (h). (g) Significant gap between the tendon edge and the bone, with a clear stump at postoperative day 10. (h) Largely atrophied muscle on post-surgery day 72.

Figure 2

Illustrative distinctive presentation of control (small letters) and BPC 157-treated rats (capital letters). Summary of the effects of controlled angiogenesis, pathologic angiogenesis (bile duct ligation-induced liver cirrhosis, 8 weeks) (control) (a,b) [118], opposed pathologic angiogenesis (BPC 157 therapy) (C,D). Gross yellow presentation of the liver and yellow ear presentation (control) (a,b), presentation of the liver and ear close to normal presentation (BPC 157 therapy) (C,D).

Figure 3

Illustrative course of 15 min following haloperidol in rats, occlusion/occlusion-like syndrome, and antecedent behavioral changes and the counteracting effect of BPC 157 therapy (10 µg/kg, 10 ng/kg ip or ig) given at 5 min after haloperidol (5 mg/kg ip) (A–N) (normal capital letter for healthy, small italic letters for control haloperidol, capital italic letters for haloperidol counteracted by BPC 157 therapy) [142]. Calvarial window brain presentation before the challenge (A), after haloperidol challenge (b) application, and after the therapy’s application (C,D), which counteracted brain swelling after BPC 157 application (italic capital letters): immediately upon BPC 157 administration (C), and further decreased brain swelling in the BPC 157 treated rat immediately before sacrifice (D). Upon sacrifice at 15 in following haloperidol, brain swelling in haloperidol rats (e) was counteracted by BPC 157 therapy (F). In microscopy studies, HE, magnification 200×, pronounced edema and congestion were visible, affecting the cerebrum, and there was more prominent intracerebral cortical hemorrhage involving larger areas of cerebral brain tissue affecting the neocortex (rectangle area) (g). BPC 157 (H). Only mild edema and congestion were found, with small, focal, and superficial areas of neocortical hemorrhage (rectangular areas and black arrow). Illustrative presentation of the recovery of vascular failure (arrows) presenting a collapsed azygos vein in haloperidol rats (i), recovered to an activated azygos vein (and, therefore, azygos vein direct blood flow delivery) in BPC 157 rats (J). Furthermore, the superior mesenteric vein (SMV) and inferior caval vein (ICV), which were congested in haloperidol rats (k), recovered to normal vein presentation in BPC 157 rats (L). Likewise, the inferior caval vein (ICV) was congested and the abdominal aorta (AA) collapsed in haloperidol rats (m); the inferior caval vein (ICV) recovered to normal presentation, and the abdominal aorta (AA) appeared activated in BPC 157 rats (N). An illustrative outcome was the evidence that BPC 157 therapy counteracted occlusion/occlusion-like syndrome as a whole for each organ involved, including brain, heart, lung, liver, kidney, and gastrointestinal tract lesions and hemorrhage, and did not produce any adverse effects on account of its beneficial effects. Moreover, intracranial (superior sagittal sinus), portal, and caval hypertension, aortal hypotension, and thrombosis were eliminated/attenuated, and thus advanced Virchow triad circumstances were fully reversed. Similar beneficial results were obtained in the counteraction of occlusion/occlusion-like syndrome induced by other neuroleptics (i.e., fluphenazine, clozapine, risperidone, olanzapine, quetiapine, and aripiprazole, but also domperidone and amphetamine [142].

Figure 4

Summary of BPC 157, a cytoprotection mediator (small black box), pleiotropic beneficial effects anchored to its resolving effects on increased angiogenesis, increased VEGF, increased egr-1 gene, increased NO, or eNOS stimulation, and increased free radical formation. Commonly, the pleiotropic issue of healing (i.e., specifically, maintaining/reestablishing tissue integrity) remains a central challenge in pharmacology (black box), particularly when the process is misdirected or not properly controlled (red lines, arrows, and boxes). The specific issue could be a strong increasing effect on particular targets, increasing angiogenesis, increased VEGF, increased egr-1 gene, increased NO or eNOS stimulation, and increased free radical formation (red boxes to indicate adverse outcomes, dashed to indicate counteraction by BPC 157 therapy). Therefore, all of these items (blue boxes), properly accommodated by BPC 157 therapy (i.e., cytoprotection concept implementation, regulation of the increasing angiogenesis, increased VEGF, increased egr-1 gene, increased NO, or eNOS stimulation, and counteraction of the increased free radical formation), might be a key to resolving beneficial action (blue lines and arrows). This might be the updated concept of cytoprotection as, long ago, innate epithelial and endothelial cell protection was postulated in the stomach. This might include targeting angiogenesis and NO’s cytotoxic and damaging actions but maintaining, promoting, or recovering their essential protective functions. Thus, this would occur as a highly controlling beneficial action, activating an effect ascribed to BPC 157 therapy’s effect depending on the disturbed circumstances. Manifest risks of unanticipated adverse effects due to pleiotropic effects and interaction with multiple systems did not occur. BPC 157 therapy’s effects are safe concerning the cure of each organ involved, including the brain, heart, lung, liver, kidney, and gastrointestinal tract, and they do not produce any adverse effect on account of its beneficial effects, along with other findings, i.e., so far no reported adverse effects in basic research, LD1 not achieved, no adverse effects in clinical trials.