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.

Cauterization of three episcleral veins (open-angle glaucoma model) induces venous congestion and increases intraocular pressure in rats. If not upgraded, one episcleral vein is regularly unable to acquire and take over the whole function, and glaucoma-like features persist. Recently, the rapid upgrading of the collateral pathways by a stable gastric pentadecapeptide BPC 157 has cured many severe syndromes induced by permanent occlusion of major vessels, veins and/or arteries, peripherally and centrally. In a six-week study, medication was given prophylactically (immediately before glaucoma surgery, i.e., three episcleral veins cauterization) or as curative treatment (starting at 24 h after glaucoma surgery). The daily regimen of BPC 157 (0.4 µg/eye, 0.4 ng/eye; 10 µg/kg, 10 ng/kg) was administered locally as drops in each eye, intraperitoneally (last application at 24 h before sacrifice) or per-orally in drinking water (0.16 µg/mL, 0.16 ng/mL, 12 mL/rat until the sacrifice, first application being intragastric). Consequently, all BPC 157 regimens immediately normalized intraocular pressure. BPC 157-treated rats exhibited normal pupil diameter, microscopically well-preserved ganglion cells and optic nerve presentation, normal fundus presentation, normal retinal and choroidal blood vessel presentation and normal optic nerve presentation. As leading symptoms, increased intraocular pressure and mydriasis, as well as degeneration of retinal ganglion cells, optic nerve head excavation and reduction in optic nerve thickness, generalized severe irregularity of retinal vessels, faint presentation of choroidal vessels and severe optic nerve disc atrophy were all counteracted. In conclusion, we claim that the reversal of the episcleral veins cauterization glaucoma appeared as a consequence of the BPC 157 therapy of the vessel occlusion-induced perilous syndrome.

Recently, stable gastric pentadecapeptide BPC 157 therapy by activation of collateral pathways counteracted various occlusion/occlusion-like syndromes, vascular, and multiorgan failure, and blood pressure disturbances in rats with permanent major vessel occlusion and similar procedures disabling endothelium function. Thereby, we revealed BPC 157 cytoprotective therapy with strong vascular rescuing capabilities in glaucoma therapy. With these capabilities, BPC 157 therapy can recover glaucomatous rats, normalize intraocular pressure, maintain retinal integrity, recover pupil function, recover retinal ischemia, and corneal injuries (i.e., maintained transparency after complete corneal abrasion, corneal ulceration, and counteracted dry eye after lacrimal gland removal or corneal insensitivity). The most important point is that in glaucomatous rats (three of four episcleral veins cauterized) with high intraocular pressure, all BPC 157 regimens immediately normalized intraocular pressure. BPC 157-treated rats exhibited normal pupil diameter, microscopically well-preserved ganglion cells and optic nerve presentation, normal fundus presentation, nor- mal retinal and choroidal blood vessel presentation, and normal optic nerve presentation. The one episcleral vein rapidly upgraded to accomplish all functions in glaucomatous rats may correspond with occlusion/occlusion-like syndromes of the activated rescuing collateral pathway (azygos vein direct blood flow delivery). Normalized intraocular pressure in glaucomatous rats corresponded to the counteracted intra-cranial (superior sagittal sinus), portal, and caval hypertension, and aortal hypotension in occlusion/occlusion-like syndromes, were all attenuated/eliminated by BPC 157 therapy. Furthermore, given in other eye disturbances (i.e., retinal ischemia), BPC 157 instantly breaks a noxious chain of events, both at an early stage and an already advanced stage. Thus, we further advocate BPC 157 as a therapeutic agent in ocular disease.

To better address the challenge of corneal ulcer healing, with already available standard agents, and those recently introduced, such as stable gastric pentadecapeptide BPC 157, we introduced a novel conceptual framework—the “triad” of corneal ulcer healing↔corneal neovascularization↔intraocular pressure—and extended it to avascular tissues such as tendon. Within this framework, cytoprotection serves as the unifying principle, underscoring that therapeutic effects are not isolated but interconnected. Preclinical studies with BPC 157 therapy, as a cytoprotection agent, illustrate this integration. BPC 157 rapidly normalizes elevated intraocular pressure in glaucomatous rats, preserves retinal integrity, restores pupil function, maintains corneal transparency during ulcer or abrasion healing, and counteracts both corneal neovascularization and dry eye. In parallel, its consistent efficacy in tendon injury models highlights a cytoprotective specificity across avascular tissues. The cornea’s “angiogenic privilege,” preserved during healing and tendon recovery together, provides strong proof of concept. Furthermore, mapping standard therapeutic agents used for corneal ulcers, neovascularization, or glaucoma onto this triad, and linking them with tendon healing, reveals both shared pathways and inconsistencies across existing drug classes. Analyzed were the ascorbate, fibronectin, hyaluronic acid, metalloproteinase inhibitors, EGF, FGF, NGF, insulin, and IGF-1 (corneal ulcer healing), the antiangiogenic agents (endostatin, PAI-1, PEDF, angiostatin, TSP-1, TSP-2, IFN-α), corticosteroids, NSAIDs, cyclosporine A, anti-VEGF drops (treatment of corneal neovascularization), and alpha 2-agonists, beta-blockers, carboanhydrase inhibitors, muscarinic agonists, Rho-kinase inhibitors, and prostaglandin analogs (glaucoma). Taken together, these findings advance cytoprotection as a unifying therapeutic paradigm, with BPC 157 emerging as its first exemplar, and encourage further translational research toward clinical application.

Introduction: We documented that stable gastric pentadecapeptide BPC 157 in rats with episcleral veins cauterization, glaucoma model, preserved retinal and optic nerve integrity. BPC 157 (LD1 not achieved) was implemented as an anti‐ulcer peptide in IBD trials and now in a multiple sclerosis trial (Curr Pharm Des 2018;24(18):1990–2001). Likewise, beneficial effects of BPC 157 on ocular tissues (Eur J Pharmacol 2016; 771: 211–9; Exp Eye Res 2015;136:9–15; Coll Antropol. 2005;29:321–5) are an especial argument. BPC 157 maintained corneal transparency, total debridement of corneal epithelium cured with no corneal neovascularization, perforating corneal incisions in rats successfully closed and no new vessels, providing a particular healing and vascular effect. Previously, in both short and prolonged terms (6 months), BPC 157 counteracts increased intraocular pressure (IOP) in rats underwent episcleral veins cauterization (FASEB J 2016, 30 (1 suppl), 1201.4; 2017, FASEB J 31 (1 suppl), 666.2). Now, rats underwent episcleral veins cauterization instead exhibiting ganglion cell layer and optic nerve thinning/atrophy, showed close to normal ganglion cell layer and optic nerve thickness, given daily, in the period of 24 h, 4 and 6 weeks. Methods: Randomly assigned operated male Wistar rats, 250g, (two dorsal episcleral veins and one temporal episcleral vein isolated from the surrounding tissues; a cautery specifically applied to the selected vein), were further studied. Now, medication (pentadecapeptide BPC 157 (10μg/kg) (Diagen, Slovenia) intraperitoneally) or an equivolume of 0.9%NaCl (5ml/kg) intraperitoneally (controls)) was applied immediately after surgery, and then once time daily. Histopathological retinal and optic nerve samples were obtained after sacrifice at 24h, 4 and 6‐weeks interval. Results: At 24h, 4 and 6 weeks after surgery controls exhibited ganglion cell layer (at 24 h 31.43±1.92 mcm; 4 weeks 21.71±3.73 mcm; 6 weeks 20.43±2.93) and optic nerve thinning (at 24h 735±19.5 mcm; 4 weeks 453.14±7.04 mcm; 6 weeks 421.71±5.99 mcm). All BPC 157 rats exhibited only slight or none ganglion cell layer (at 24 h 41±5.15 mcm; 4 weeks 33±0.76 mcm; 6 weeks 31.14±1.11 mcm) or optic nerve thinning (at 24 h 763±10.80 mcm; 4 weeks 731.86±16.05 mcm; 6 weeks 732.86±7.24 mcm). Differences were statistically significant between control and BPC 157 treated animals at an interval of 4 and 6 weeks (p<0,05). So we conclude that microscopy analysis correlates well with ophthalmoscopy findings published in our previous research (i.e., BPC 157 groups diameter of the optic nerve remained close to normal unlike control's atrophy/thinning of the ganglion cell layer and optic nerve) (Figure 1: Rat optic nerve presentation at 6 weeks, HEx20, saline application (right), BPC 157 regimen (left)). Conclusion: Pentadecapeptide BPC 157 continuously counteracts the effects of episcleral veins cauterization on morphological changes of ganglion cell layer and optic nerve. Support or Funding Information Ministry of Science, Education and Sports, Republic of Croatia [grant number 108‐1083570‐3635]. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .