Vjekoslav Jagić

The influence of a novel pentadecapeptide, BPC 157, on NG-nitro-l-arginine methylester and l-arginine effects on stomach mucosa integrity and blood pressure

The known effects of a novel stomach pentadecapeptide BPC157 (10 microg or 10 ng/kg), namely its salutary activity against ethanol (96%, i.g.)-induced gastric lesions (simultaneously applied i.p.) and in blood pressure maintenance (given i.v.), were investigated in rats challenged with a combination of N(G)-nitro-L-arginine methylester (L-NAME) (5 mg/kg i.v.), a competitive inhibitor of endothelium nitric oxide (NO)-generation and NO precursor, L-arginine (200 mg/kg i.v.) (D-arginine was ineffective). In the gastric lesions assay, NO agents were given 5 min before ethanol injury and BPC 157 medication. Given alone, BPC157 had an antiulcer effect, as did L-arginine, but L-NAME had no effect. L-NAME completely abolished the effect of L-arginine, whereas it only attenuated the effect of BPC 157. After application of the combination of L-NAME + L-arginine, the BPC157 effect was additionally impaired. In blood pressure studies, compared with L-arginine, pentadecapeptide BPC 157 (without effect on basal normal values) had both a mimicking effect (impaired L-NAME-blood pressure increase, when applied prophylactically and decreased already raised L-NAME values, given at the time of the maximal L-NAME-blood pressure increase (i.e., 10 min after L-NAME)) and preventive activity (L-arginine-induced moderate blood pressure decrease was prevented by BPC 157 pretreatment). When BPC 157 was given 10 min after L-NAME + L-arginine combination, which still led to a blood pressure increase, its previously clear effect (noted in L-NAME treated rats) disappeared. In vitro, in gastric mucosa from rat stomach tissue homogenates, BPC 157, given in the same dose (100 microM) as L-arginine, induced a comparable generation of NO. But, BPC 157 effect could not be inhibited by L-NAME, even when L-NAME was given in a tenfold (100 versus 1000 microM) higher dose than that needed for inhibition of the L-arginine effect. NO synthesis was blunted when the pentadecapeptide BPC 157 and L-arginine were combined. In summary, BPC 157 could interfere with the effects of NO on both gastric mucosal integrity and blood pressure maintenance in a specific way, especially with L-arginine, having a more prominent and/or particularly different effect from that of NO.

The beneficial effect of BPC 157, a 15 amino acid peptide BPC fragment, on gastric and duodenal lesions induced by restraint stress, cysteamine and 96% ethanol in rats. A comparative study with H2 receptor antagonists, dopamine promotors and gut peptides

The protection of stomach and duodenum in conjecture with anti-inflammatory effect was demonstrated for a novel 15 amino acid peptide, coded BPC 157, a fragment of the recently discovered gastric juice peptide BPC. BPC 157 (i.p./i.g.) was investigated in rats in comparison with several reference standards in three experimental ulcer models (48 h-restraint stress, subcutaneous cysteamine, intragastrical 96% ethanol ulcer tests) (pre-/co-/post-treatment). Only BPC 157 regimens were consistently effective in all of the tested models. On the other hand, bromocriptine, amantadine, famotidine, cimetidine and somatostatin were ineffective (restraint stress). A dose-dependent protection (cysteamine) and/or partial positive effect (related to treatment conditions) (ethanol), was obtained with glucagon, NPY and secretin whereas CCK/26-30/was not effective. Based on Monastral blue studies BPC 157 beneficial effect appears to be related to a strong endothelial protection.

Beneficial effect of a novel pentadecapeptide BPC 157 on gastric lesions induced by restraint stress, ethanol, indomethacin, and capsaicin neurotoxicity

Very recently, the integrity of capsaicin somatosensory neurons and their protection were suggested to be related to the activity in nociception of a newly discovered 15-amino acid peptide, BPC 157, shown to have strong beneficial effect on intestinal and liver lesions. Therefore, from this viewpoint, we have studied the gastroprotective effect of the pentadecapeptide BPC 157, on gastric lesions produced in rats by 96% ethanol, restraint stress, and indomethacin. The possible involvement of sensory neurons in the salutary actions of BPC 157 (10µg/kg, 10 ng/kg intraperitoneally) was studied with capsaicin, which has differential effects on sensory neurons: a high dose in adult (125 mg/kg subcutaneously, 3 months old) or administration (50 mg/kg subcutaneously) to neonatal animals (age of the 7 days) destroys sensory fibers, whereas a low dose (500µg/kg intraperitoneally) activates neurotransmitter release and protective effects on the mucosa. In the absence of capsaicin, BPC 157 protected gastric mucosa against ethanol, restraint, and indomethacin application. In the presence of neurotoxic doses of capsaicin, the negative influence of capsaicin on restraint, ethanol, or indomethacin lesions consistently affected salutary activity of BPC 157. However, BPC 157 protection was still evident in the capsaicin-treated rats (either treated as adults or as newborns) in all of these assays. Interestingly, after neonatal capsaicin treatment, a complete abolition of BPC gastroprotection was noted if BPC 157 was applied as a single nanogram-regimen, but the mucosal protection was fully reversed when the same dose was used daily. In line with the excitatory dose of capsaicin the beneficial effectiveness of BPC 157 appears to be increased as well. Taken together, these data provide evidence for complex synergistic interaction between the beneficial effectiveness of BPC 157 and peptidergic sensory afferent neuron activity.

Hepatoprotective effect of BPC 157, A 15-aminoacid peptide, on liver lesions induced by either restraint stress or bile duct and hepatic artery ligation or CCl4 administration. A comparative study with dopamine agonists and somatostatin

The hepatoprotective effects of a newly synthesized 15 amino acid fragment code named BPC 157 was evaluated in comparison with the reference standards (bromocriptine, amantadine and somatostatin) in various experimental models of liver injury in rats: 24 h-bile duct+hepatic artery ligation 48 h-restraint stress and CCl4 administration. BPC 157 administered either intragastrically or intraperitoneally, significantly prevented the development of liver necrosis or fatty changes in rats subjected to 24 h bile duct + hepatic artery ligation, 48 h-restraint stress, CCl4 treatment (1 ml/kg i.p., sacrifice 48 h thereafter). The other reference drugs had either little or no protective actions in these models. Noteworthy, the laboratory test results for bilirubin, SGOT, SGPT fully correlated with the macro/microscopical findings. Thus, on the basis of consistent protective effect of BPC 157, possible clinical application in liver diseases is now warranted.

Pentadecapeptide BPC 157 positively affects both non-steroidal anti-inflammatory agent-induced gastrointestinal lesions and adjuvant arthritis in rats

Besides a superior protection of the pentadecapeptide BPC 157 (an essential fragment of an organoprotective gastric juice peptide BPC) against different gastrointestinal and liver lesions, an acute anti-inflammatory and analgetic activity was also noted. Consequently, its effect on chronic inflammation lesions, such as adjuvant arthritis, and non-steroidal anti-inflammatory agents (NSAIAs)-induced gastrointestinal lesions was simultaneously studied in rats. In gastrointestinal lesions (indomethacin (30 mg/kg s.c.), aspirin (400 mg/kg i.g.) and diclofenac (125 mg/kg i.p.) studies, BPC 157 (10 micrograms or 10 ng/kg i.p.) was regularly given simultaneously and/or 1 h prior to drug application (indomethacin). In the adjuvant arthritis (tail-application of 0.2 mL of Freunds adjuvant) studies (14 days, 30 days, 1 year) BPC 157 (10 micrograms or 10 ng/kg i.p.), it was given as a single application (at 1 h either before or following the application of Freunds adjuvant) or in a once daily regimen (0-14th day, 14-30th day, 14th day-1 year). Given with the investigated NSAIAs, BPC 157 consistently reduced the otherwise prominent lesions in the stomach of the control rats, as well as the lesions in the small intestine in the indomethacin groups. In the adjuvant arthritis studies, the lesions development seems to be considerably reduced after single pentadecapeptide medication, and even more attenuated in rats daily treated with BPC 157. As a therapy of already established adjuvant arthritis, its salutary effect consistently appeared already after 2 weeks of medication and it could be clearly seen also after 1 year of application. Taking together all these results, the data likely point to a special anti-inflammatory and mucosal integrity protective effect.

Pentadecapeptide BPC 157, Cimetidine, Ranitidine, Bromocriptine, and Atropine Effect in Cysteamine Lesions in Totally Gastrectromized Rats (A Model for Cytoprotective Studies)

A superior effectiveness in various lesionassays was noted for the novel pentadecapeptide BPC 157,originated from human gastric juice protein (BPC) andclaimed to be a cytoprotective agent. From this viewpoint, as a previously untreatedexperimental improvement to create an acid-freeenvironmental for cytoprotection studies, totalgastrectomy was done 24 hr before the ulcerogenicprocedure. In the absence of stomach and gastric acid, the damagingeffects of cysteamine (400 mg/kg subcutaneously, death24 hr thereafter), to date thought to be an acid-relatedduodenal ulcerogen, and the BPC 157 cytoprotective effect (10 mug or 10 ng/kg intraperitoneally)were further challenged. BPC 157 was compared withreference agents [cimetidine (50), ranitidine (10),omeprazole (10), bromocriptine (10) and atropine (10) (mg/kg intraperitoneally, 1 hr beforecysteamine] known to be also cytoprotective. In naiverats, with intact stomach, all of them showed a strongbeneficial effect. Interestingly, in gastrectomizedanimals, the application of BPC 157 or the referenceagents before cysteamine significantly prevented theotherwise severe duodenal lesion development noted inthe control gastrectomized cysteamine rats. In groups without cysteamine, no lesions were noted(laparotomy, gastrectomy only, 24 or 48 hr postsurgicalperiod), nor was lesion potentiation seen incysteamine-treated laparotomized animals. In summary,these findings -- equal damaging effect ofcysteamine and equal protection of pentadecapeptide BPC157 and reference agents in gastrectomized and rats withintact stomach -- seem to be particularly relevantfor a cytoprotective viewpoint. Without a stomach,the cysteamine damaging effect was convincingly definedas an essential gastric acid-independent injury(analogous to ethanol gastric lesions). Likewise, a high “cytoprotective capacity,”apparently acid independent, common for all testedagents (novel pentadecapeptide BPC 157, cimetidine,ranitidine, omeprazole and atropine) could be clearlystressed.

Salutary and prophylactic effect of pentadecapeptide BPC 157 on acute pancreatitis and concomitant gastroduodenal lesions in rats

The superior effectiveness of a new pentadecapeptide, BPC 157, on gastrointestinal and liver lesions, in conjunction with an antiinflammatory and analgetic activity was recently noted. In the present study, BPC 157 was tested as either a protective or healing agent in bile duct ligation-induced acute pancreatitis in rats. In addition, the positive influence of BPC 157 on concomitantly developed gastric and duodenal lesions was simultaneously investigated. BPC 157 (10 µg, 10 ng/kg body wt, intraperitoneally or intragastrically) was given prophylactically 1 hr before ligation, whereas the therapy was given once daily beginning with the 24 hr following ligation (last application 24 hr before killing). The effect was investigated at daily intervals until the end of the fifth day after ligation. In the pretreatment regimen, a strong pancreas protection was obtained. When applied in the condition of already established severe acute pancreatitis, an obvious salutary effect was consistently noted. Assessing the appearance of the necrosis, edema, neutrophils, and mononuclears, consistently less necrosis, edema, and neutrophils, but more mononuclears, were found in BPC-treated rats. Likewise, in studies of the serum amylase values, relative to control data, a markedly lower rise (BPC pretreatment regimen) as well as a worsening of the already raised values (BPC therapy regimen) was noted. Along with its beneficial effect on pancreatitis, a positive influence of BPC 157 on the gastric and duodenal lesion course in bile duct-ligated rats was noted in both the pre- and posttreatment regimen. Taken together, in further studies of acute pancreatitis therapy, BPC could be an interesting and useful agent with an additional positive impact on concomitant gastroduodenal pathology.

A behavioural study of the effect of pentadecapeptide BPC 157 in Parkinson's disease models in mice and gastric lesions induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

The effect of a stomach pentadecapeptide, BPC 157, on Parkinsons disease in mice was investigated, along with its salutary activity on stomach lesions induced by parkinsongenic agents. Parkinsongenic agents, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (30.0 mg x kg(-1)b.w. i.p. once daily for 6d, and after 4d once 50.0 mg x kg(-1)b.w. i.p.) or reserpine (5.0 mg x kg(-1)b.w. i.p.) were applied i.p. BPC 157 (1.50 microg or 15.0 ng x kg(-1)b.w. i.p.) was applied 15 min before or alternatively 15 min after each MPTP administration. In reserpine studies, BPC 157 (10.0 microg or 10.0 ng x kg(-1)b.w. i.p.) was given either 15 min before reserpine or in the already established complete catalepsy 24 h thereafter. BPC 157 strongly improved the MPTP-impaired somatosensory orientation and reduced the MPTP-induced hyperactivity, and most importantly, MPTP-motor abnormalities (tremor, akinesia, catalepsy -otherwise very prominent in saline control), leading to almost complete abolition of otherwise regularly lethal course of MPTP treatment in controls. Likewise, in reserpine experiments, BPC 157 strongly prevented the development of otherwise very prominent catalepsy and when applied 24 h thereafter reversed the established catalepsy. In addition, a reduction of reserpine-hypothermy (BPC 157 pre-treatment) and reversal of further prominent temperature fall (BPC 157 post-treatment) have been consistently observed. Taking together these data, as the two most suitable animal models were consistently used and since the high effectiveness was demonstrated in pre- and post-treatment, microg and ng regimens, BPC 157 as an organoprotector should be further therapeutically investigated. Additionally, given in either regimen, pentadecapeptide BPC 157 strongly attenuated the stomach lesions in mice that otherwise consistently appeared in mice treated with the parkinsogenic neurotoxin MPTP.

Dopamine agonists prevent duodenal ulcer relapse. A comparative study with famotidine and cimetidine.

The present study investigated both the healing rate (after four weeks) and the relapse rate (during six months) following treatment with the dopamine-like drugs bromocriptine (2.5 mg twice daily), amantadine (100 mg nocte), or with the H2 blockers cimetidine (800 mg nocte), and famotidine (40 mg nocte) in 124 patients with endoscopically proven duodenal ulcer (DU). The ulcer was completely healed in 27 (amantadine), 26 (bromocriptine), 23 (cimetidine), and in 24 (famotidine) patients. Relapse was noted in 34.7% (cimetidine) and 25% (famotidine) versus 11.7% (amantadine) and 7.7% (bromocriptine) DU patients. No significant difference was found in initial healing rates. However, the relapse rate in the cimetidine-treated group was significantly higher than in all the other test groups. Additional comparisons between all the treatment categories showed a significantly lower relapse rate with the dopamine-like agents. These important new results indicate that dopamine-like compounds are equally effective as H2 blockers in inducing DU healing and may offer a promising advantage over H2 blockers concerning their efficacy in preventing ulcer relapse in DU patients.

The effect of pentadecapeptide BPC 157 on inflammatory, non-inflammatory, direct and indirect pain and capsaicin neurotoxicity

The anti-nociceptive effects of a newly synthesized pentadecapeptide coded BPC 157 (an essential fragment of new organoprotective gastric juice peptide BPC) was evaluated in comparison with aspirin and morphine reference standards, in various experimental models of indirect/direct nociception and neurotoxicity: writhing (acetic acid/magnesium sulphate), tail pinching, hot-plate, and capsaicin application. BPC 157 administered either in the ng or μg per kg range, intraperitoneally, significantly reduced the reactions in the writhing (inflammatory and non-inflammatory, prostaglandin-dependent and independent) and tail pinching tests. In the hot-plate test, unlike morphine, BPC 157 had no effect on normal animals. However, when given to capsaicin treated rats, BPC 157 strongly reduced capsaicin-allodynia, either given as pretreatment or once daily for 14 days after the capsaicin injection. This reduction in capsaicin’s effect could not be obtained when BPC 157 was applied in the presence of established capsaicin-somatosensory neuron degeneration (application only on the 14th day after capsaicin), so it is possible that the effects of BPC 157 could be related specifically to the integrity of capsaicin-sensitive somatosensory neurons and their protection (e.g. primary afferent neurons having small-diameter somata and unmyelinated (C-) or thinly myelinated (A6-) fibres).