Protective effects of pentadecapeptide BPC 157 on gastric ulcer in rats

AIM: To investigate the protective effects of gastric pentadecapeptide BPC 157 on acute and chronic gastric ulcers in rats and to compare the results in therapy of human gastric ulcers by different administration methods. METHODS: Gastric pentadecapeptide BPC 157 was administered (initial single or continuous administration) into rats either intragastrically or intramuscularly before (induced acute gastric ulcer) or after (induced chronic gastric ulcer) the applications of inducing agents, and each animal was sacrificed to observe the protective effects of BPC 157 on gastric ulcers. RESULTS: Both intramuscular (im) and intragastric (ig) administration of BPC 157 could apparently reduce the ulcer area and accelerate the healing of induced ulcer in different models and the effect of im administered BPC 157 was better than that of ig. The rats treated with higher dosages (400 ng/kg, 800 ng/kg) of BPC 157 (im and ig) showed significantly less lesion (P<0.01 vs excipient or saline control), the inhibition ratio of ulcer formation varied between 45.7% and 65.6%, from all measurements except 400 ng/kg BPC 157 in pylorus ligation induced model (P<0.05), in which the inhibition rate was 54.2%. When im administered (800 ng/kg BPC 157) in three models, the inhibition ratio of ulcer formation was 65.5%, 65.6% and 59.9%, respectively, which was better than that of famotidine (its inhibition rate was 60.8%, 57.2% and 34.3%, respectively). Continuous application of BPC 157 (in chronic acetate induced gastric ulcer) could accelerate rebuilding of glandular epithelium and formation of granulation tissue (P<0.05 at 200 ng/kg and P<0.01 at 400 ng/kg and 800 ng/kg vs excipient or saline control). CONCLUSION: Both im and ig administered gastric pentadecapeptide BPC 157 can apparently ameliorate acute gastric ulcer in rats and antagonize the protracted effect of acetate challenge on chronic ulcer. The effect of im administration of BPC 157 is better than that of ig, and the effective dosage of the former is lower than that of the latter.     

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.This study was subsidized by grants from the Ministry of Science of the Republic of Croatia and Pliva, Zagreb, Croatia.     

Bypassing major venous occlusion and duodenal lesions in rats,and therapy with the stable gastric pentadecapeptide BPC 157, L-NAME and L-arginine

AIM To investigate whether duodenal lesions induced by major venous occlusions can be attenuated by BPC 157 regardless nitric oxide(NO) system involvement.METHODS Male Wistar rats underwent superior anterior pancreaticoduodenal vein(SAPDV)-ligation and were treated with a bath at the ligated SAPDV site(BPC 157 10 μg, 10 ng/kg per 1 mL bath/rat; L-NAME 5 mg/kg per 1 m L bath/rat; L-arginine 100 mg/kg per 1 mL bath/rat, alone and/or together; or BPC 157 10 μg/kg instilled into the rat stomach, at 1 min ligation-time). We recorded the vessel presentation(filled/appearance or emptied/disappearance) between the 5 arcade vessels arising from the SAPDV on the ventral duodenum side, the inferior anterior pancreaticoduodenal vein(IAPDV) and superior mesenteric vein(SMV) as bypassing vascular pathway to document the duodenal lesions presentation; increased NO-and oxidative stress [malondialdehyde(MDA)]-levels in duodenum.RESULTS Unlike the severe course in the SAPDV-ligated controls, after BPC 157 application, the rats exhibited strong attenuation of the mucosal lesions and serosal congestion, improved vessel presentation, increased interconnections, increased branching by more than 60% from the initial value, the IAPDV and SMV were not congested. Interestingly, after 5 min and 30 min of L-NAME and L-arginine treatment alone, decreased mucosal and serosal duodenal lesions were observed; their effect was worsened at 24 h, and no effect on the collateral vessels and branching was seen. Together, L-NAME+L-arginine antagonized each other's response, and thus, there was an NO-related effect. With BPC 157, all SAPDV-ligated rats receiving L-NAME and/or L-arginine appeared similar to the rats treated with BPC 157 alone. Also, BPC 157 in SAPDV-ligated rats normalized levels of NO and MDA, two oxidative stress markers, in duodenal tissues.CONCLUSION BPC 157, rapidly bypassing occlusion, rescued the original duodenal flow through IAPDV to SMV flow, aneffect related to the NO system and reduction of free radical formation.     

Gastric lesions induced by ethanol and indomethacin: cytoprotective effect of acetazolamide

A study was made of the effect of acetazolamide (a potent carbonic anhydrase inhibitor) on the production of lesions by absolute alcohol and of the effect of indomethacin (inhibitor of cyclooxygenase) on the gastric cytoprotection produced by S-adenosylmethionine (sulfhydryl compound). Acetazolamide significantly reduced gastric mucosa lesions induced by oral administration of absolute alcohol. It did not modify those produced by indomethacin. Pretreatment with acetazolamide potentiated the production of S-adenosylmethionine in response to alcohol injury, but it did not modify the protective effect of S-adenosylmethionine against injury by indomethacin. Since acetazolamide did not alter gastric secretion of HCO3-, it is concluded that carbonic anhydrase-dependent gastric alkali secretion did not intervene in the gastric acetazolamide-induced cytoprotective mechanism. The same effect was produced by stimulation of the biosynthesis of endogenous prostaglandins. This provides a physiologic rationale for the use of acetazolamide in acute gastric disease and gastroduodenal peptic ulcer.     

Cytoprotective gastric pentadecapeptide BPC 157 resolves major vessel occlusion disturbances,ischemia-reperfusion injury following Pringle maneuver,and Budd-Chiari syndrome

The stable gastric pentadecapeptide BPC 157 counteracts various venous occlusion-induced syndromes. Summarized are all these arguments, in the Robert’s cytoprotection concept, to substantiate the resolution of different major vessel occlusion disturbances, in particular ischemia-reperfusion injury following the Pringle maneuver and Budd-Chiari syndrome, which was obtained by BPC 157 therapy. Conceptually, there is a new point, namely, endothelium maintenance to epithelium maintenance (the recruitment of collateral blood vessels to compensate for vessel occlusion and reestablish blood flow or bypass the occluded or ruptured vessel). In this paper, we summarize the evidence of the native cytoprotective gastric pentadecapeptide BPC 157, which is stable in the human gastric juice, is a membrane stabilizer and counteracts gut-leaky syndrome. As a particular target, it is distinctive from the standard peptide growth factors, involving particular molecular pathways and controlling VEGF and NO pathways. In the early 1990s, BPC 157 appeared as a late outbreak of the Robert’s and Szabo’s cytoprotection-organoprotection concept, like the previous theoretical/practical breakthrough in the 1980s and the brain-gut axis and gut-brain axis. As the time went on, with its reported effects, it is likely most useful theory practical implementation and justification. Meantime, several reviews suggest that BPC 157, which does not have a lethal dose, has profound cytoprotective activity, used to be demonstrated in ulcerative colitis and multiple sclerosis trials. Likely, it may bring the theory to practical application, starting with the initial argument, no degradation in human gastric juice for more than 24 h, and thereby, the therapeutic effectiveness (including via a therapeutic per-oral regimen) and pleiotropic beneficial effects.     

Role of leukotrienes in acute gastric lesions induced by ethanol,taurocholate, aspirin,platelet-activating factor and stress in rats

This study was designed to determine the role of leukotriene C₄ (LTC₄) in the formation of acute gastric lesions induced by 100% ethanol, acidified taurocholate (TC), acidified aspirin (ASA), platelet-activating factor (PAF), and water-immersion and restraint stress. Exogenous LTC₄ alone administered in gradually increasing doses (5–20g/kg/hr) caused only mild hemorrhagic lesions in the gastric mucosa but when combined with 100% ethanol, acidified TC, acidified ASA, or stress, it increased significantly the mean lesion area and lesion number as compared to those produced by these ulcerogens alone. FPL 55712, a LTC₄ antagonist, given orally (2.5–10 mg/kg) reduced dose-dependently the extent of gastric lesions in all experimental models used and completely prevented the deleterious effects of exogenous LTC₄ on gastric mucosa. PAF augmented the mucosal lesions induced by 100% ethanol, and this was also reduced by the pretreatment with FPL 55712. FPL 55712-induced gastroprotection against various ulcerogens was reversed, in part, by indomethacin, indicating that it could be attributed not only to the LTC₄ antagonism but also to increased biosynthesis of PGs. This study provides evidence that LTC₄ is involved in the formation of acute gastric damage and the antagonism of LTC₄ may protect the mucosa against various ulcerogens.     

Effects of dopamine on gastric mucosal lesions induced by ethanol in rats

Acidified ethanol (60% ethanol in 150 mM HCl, per os) induced elongated bands of hemorrhagic lesions along the long axis of the stomach within 1 hr in rats. Pretreatment with dopamine hydrochloride (DA: 1-10 mg/kg, subcutaneously) dose-dependently reduced the severity of these lesions. In parallel study, DA had no effect on acid secretion but inhibited gastric motor activity in a dose-related manner. The inhibitory effects of DA on both acidified ethanol-induced lesions and gastric motor activity were significantly reversed by pretreatment with yohimbine, an inhibitor of alpha 2-adrenoceptors (5 mg/kg, subcutaneously), but not by prazosin, haloperidol, or indomethacin. Similar to DA, both norepinephrine (NE: 1 mg/kg, subcutaneously) and epinephrine (EPI: 1 mg/kg, subcutaneously) showed inhibition of the motor activity and gastroprotection against acidified ethanol, but these effects were also significantly attenuated by yohimbine. A highly significant relationship was found between the inhibitory effects of DA, NE, and EPI on the motor activity and the mucosal lesions (r = 0.8577, P less than 0.05). In addition, administration of gentian violet (0.5% w/v, per os) stained the mucosa deep blue as elongated wide bands in the corpus region, and such localized staining was significantly prevented by DA, suggesting a flattening of the mucosal foldings in the presence of DA. These results suggest that DA (and other catecholamines) protects the rat gastric mucosa against injury caused by acidified ethanol, probably through inhibition of gastric motor activity mediated with stimulation of alpha 2-adrenoceptors.     

Celecoxib-induced gastrointestinal,liver and brain lesions in rats,counteraction by BPC 157 or L-arginine,aggravation by L-NAME

AIM To counteract/reveal celecoxib-induced toxicity and NO system involvement. METHODS Celecoxib(1 g/kg b.w. ip) was combined with therapy with stable gastric pentadecapeptide BPC 157(known to inhibit these lesions, 10 μg/kg, 10 ng/kg, or 1 ng/kg ip) and L-arginine(100 mg/kg ip), as well as NOS blockade [N(G)-nitro-L-arginine methyl ester(L-NAME)](5 mg/kg ip) given alone and/or combined immediately after celecoxib. Gastrointestinal, liver, and brain lesions and liver enzyme serum values in rats were assessed at 24 h and 48 h thereafter. RESULTS This high-dose celecoxib administration, as a result of NO system dysfunction, led to gastric, liver, and brain lesions and increased liver enzyme serum values. The L-NAME-induced aggravation of the lesions was notable for gastric lesions, while in liver and brain lesions the beneficial effect of L-arginine was blunted. L-arginine counteracted gastric, liver and brain lesions. These findings support the NO system mechanism(s), both NO system agonization(L-arginine) and NO system antagonization(L-NAME), that on the whole are behind all of these COX phenomena. An even more complete antagonization was identified with BPC 157(at both 24 h and 48 h). A beneficial effect was evident on all the increasingly negative effects of celecoxib and L-NAME application and in all the BPC 157 groups(L-arginine + BPC 157; L-NAME + BPC 157; L-NAME + L-arginine + BPC 157). Thus, these findings demonstrated that BPC 157 may equally counteract both COX-2 inhibition(counteracting the noxious effects of celecoxib on all lesions) and additional NOS blockade(equally counteracting the noxious effects of celecoxib + L-NAME). CONCLUSION BPC 157 and L-arginine alleviate gastrointestinal, liver and brain lesions, redressing NSAIDs' post-surgery application and NO system involvement.     

Effect of capsaicin and chilli on ethanol induced gastric mucosal injury in the rat.

Capsaicin, the pungent ingredient of chilli, is gastroprotective against experimental gastric injury when given intragastrically. Epidemiological and clinical data suggest that chilli ingestion may have a beneficial effect on human peptic ulcer disease. This study showed a gastroprotective effect of intragastric capsaicin, in doses of 2 and 5 mg, on ethanol induced gastric mucosal injury using macroscopic, histological, scanning electron microscopic, and biochemical indices. Subcutaneous administration of 2 mg of capsaicin had the same gastroprotective effect as intragastric administration. Acute intragastric administration and chronic ingestion of chilli powder in doses comparable with that consumed in humans (up to 200 mg in single doses or 200 mg daily for four weeks) likewise protected the gastric mucosa. Both the mucosa and gastric juice had higher mucus contents when capsaicin or chilli rather than saline or solvent was used before ethanol challenge. In control animals capsaicin also increased gastric juice mucus content although the mucosal content was unaffected. Increased gastric mucus production may therefore be one mechanism by which capsaicin and chilli exert their gastroprotective effect although an alternative explanation is that the reduction in mucosal mucus depletion is secondary to the protective effect of capsaicin and chilli.     

Role of prostaglandin deficiency in pathogenetic mechanism of gastric lesions induced by indomethacin in rats

The present study was undertaken in rats using 2-deoxy-D-glucose (2DG) as a stimulator of gastric motility and a low dose of indomethacin as a prostaglandin (PG) synthesis inhibitor to investigate the roles of gastric motility and PG deficiency in the pathogenesis of indomethacin-induced gastric lesions. Subcutaneously administered indomethacin at 5 mg/kg did not induce any visible damage in the mucosa within 4 hr, but at 25 mg/kg produced linear hemorrhagic lesions along the long axis of the stomach. 2DG (100 mg/kg/hr), given intravenously, produced linear nonhemorrhagic lesions along the mucosal folds and, in the presence of 5 mg/kg of indomethacin, caused severe hemorrhagic lesions in the same areas of the stomach. Gastric motility was markedly enhanced by both indomethacin (25 mg/kg) and 2DG, while acid output and mucosal blood flow were increased only by the latter. Mucosal PGE ₂ levels were significantly reduced by indomethacin (25 mg/kg) but not by 2DG. Indomethacin at 5 mg/kg alone had no or little effect on any parameter except PG levels, which were reduced to similar degrees as caused by 25 mg/kg of the agent. Time-course development of the lesions was closely associated with those changes in gastric motility after administration of indomethacin (25 mg/kg) and 2DG. These results suggest that the enhanced gastric motility is, by itself, sufficient to induce damage (nonhemorrhagic) in the mucosa and that a PG deficiency alone does not induce any damage but is required for further extension to hemorrhagic lesions of nonhemorrhagic ones that are initially induced by enhanced gastric motility.     

Bilateral adrenalectomy worsens gastric mucosal lesions induced by indomethacin in the rat. Role of enhanced gastric motility

The mechanism by which bilateral adrenalectomy worsens indomethacin-induced gastric lesions was investigated in rats. In sham-operated rats subcutaneously administered indomethacin produced gastric lesions at doses of 10 mg/kg body wt or greater, in association with lowering of blood glucose levels. In a parallel study, indomethacin induced gastric hypermotility at the same dose levels but had no effect on acid output or mucosal blood flow even at 25 mg/kg body wt. Adrenalectomy (2 wk) itself significantly reduced the blood glucose levels (approximately 50%) and markedly potentiated the ulcerogenic and motility responses caused by indomethacin; the ED50 values dropped to approximately 10 times lower than those in sham-operated rats. Both acid output and mucosal blood flow were significantly reduced by adrenalectomy, but these values were increased after indomethacin treatment (3 mg/kg body wt). The ulcerogenic and motility responses caused by indomethacin were significantly reduced by acute infusion of glucose (25% wt/wt, 1.2 ml/h) intravenously in both sham-operated and adrenalectomized rats, and by subcutaneous administration of hydrocortisone acetate (10 mg/kg body wt for 2 wk) in the latter group. When the motility and the ulcer score were determined in the same animals, a highly significant relationship was found between these two factors in both sham-operated and adrenalectomized rats. These results suggest that (a) the increased gastric motility may be a key element in the pathogenesis of indomethacin-induced lesions and in the mechanism for aggravation of the lesions and in the mechanism for aggravation of the lesions by adrenalectomy, and (b) abrasion of adrenal glands by inducing hypoglycemia may sensitize the system to indomethacin and increase gastric motility.     

Bosentan, a novel synthetic mixed-type endothelin receptor antagonist, attenuates acute gastric mucosal lesions induced by indomethacin and HCl in the rat: Role of endogenous endothelin-1

Endothelin-1 has been reported to be responsible for gastric mucosal damage in various experimental models. We evaluated the role of endogenous endothelin-1 in the pathogenesis of gastric mucosal damage induced by indomethacin and HCl in the rat. Rats were given indomethacin (25 mg/kg) subcutaneously, and 15 min later, 0.2N HCl intragastrically. Gastric mucosal damage, gastric endogenous endothelin-1, and gastric mucosal hemodynamics were measured. The effects of bosentan, a mixed endothelin receptor antagonist, on gastric mucosal integrity and hemodynamics were assessed. Gastric endogenous endothelin-1 was significantly elevated at 20min, gastric mucosal blood flow began to decrease significantly at 25 min, and gastric damage occupied 52.2% of the total glandular mucosa at 135 min after injection of indomethacin. Intragastric pretreatment with bosenthan (5, 10, 30, and 60 mg/kg) significantly attenuated gastric damage, to 26.1%, 7.7%, 3.6%, and 1.6%, respectively, of the total glandular mucosa. Bosentan (60 mg/kg) prevented the initial decrease of blood flow and, even at 135 min, improved blood flow and hemoglobin oxygen saturation significantly. We suggest that indomethacin-induced endogenous endothelin-1 diminishes gastric mucosal blood flow and tissue oxygenation and ultimately causes gastric damage. Endogenous endothelin-1 may play an important role in the pathogenesis of the acute gastric mucosal lesions induced by indomethacin and HCl.     

Effect of teprenone on acute gastric mucosal lesions induced by cold-restraint stress.

The effects of intragastric administration of teprenone on acute gastric mucosal lesions induced by cold-restraint stress was investigated using a model of obstructive jaundice. Rats received teprenone 200 mg/kg/day for a week before stress; nontreated rats served as controls. Teprenone suppressed stress-induced depressions in defensive factors (blood flow, transmucosal potential difference, hexosamine content and lectin staining of carbohydrate residues) and suppressed increases in lesion-enhancing factors (gastric mucosal lysosomal enzyme activity and thiobarbituric acid reactants showing lipid peroxidation). Intragastric pH did not change significantly with teprenone but the ulcer index decreased. These results showed that teprenone protects gastric mucosa against stress, even in the presence of obstructive jaundice.     

Role of endogenous gastric mucosal prostaglandins in the formation of acute gastric mucosal lesions induced by aspirin, ethanol, HCl and CH3COOH

The role of endogenous mucosal prostaglandins (PGs) in the production of acute gastric mucosal lesions (AGML) was examined in rats. Aspirin, ethanol or 0.6 N-HCl was given intragastrically and 20% acetic acid was injected into the gastric wall. Endogenous gastric mucosal PG (A + B), PGE and PGF were determined by radioimmunoassay. Their gastric contents were markedly reduced by aspirin administration (p less than 0.001). The level of gastric mucosal PGs still remained low (p less than 0.001) after the aspirin-induced AGML began to heal. Furthermore, rats with AGML induced by ethanol, HCl or acetic acid, showed no decrease in endogenous gastric mucosal PGs compared with the controls. These findings indicated that endogenous PGs are not necessary for either the induction or healing of experimental AGML.     

Protective effects of amphetamine on gastric ulcerations induced by indomethacin in rats

INTRODUCTION The involvement of the adrenergic system in some models of gastric ulcerations is well documented[1-4]. Our previous investigations have shown that amphetamine, an indirectly acting sympathomimetic amine has a protective activity on gastric u…