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Counteraction of perforated cecum lesions in rats: Effects of pentadecapeptide BPC 157,L-NAME and L-arginine

World Journal of Gastroenterology 2018年第48期24卷 5462-5476页

作者： Domagoj Drmic Mariam Samara Tinka Vidovic Dominik Malekinusic Marko Antunovic Borna Vrdoljak Jelena Ruzman Marija Milkovic Perisa katarina horvat pavlov Jerusha Jeyakumar Sven Seiwerth Predrag Sikiric Departments of Pharmacology and Pathology Medical Faculty University of Zagreb

AIM To study the counteraction of perforated cecum lesion using BPC 157 and nitric oxide(NO) system *** Alongside with the agents' application(after 1 min, medication(/kg, 10 ml/2 min bath/rat) includes: BPC 157(10 μg), L-NAME(5 mg), L-arginine(100mg) alone or combined, and saline baths(controls)) on the rat perforate cecum injury, we continuously assessed the gross reappearance of the vessels(USB microcamera) quickly propagating toward the defect at the cecum surface, defect contraction, bleeding attenuation, MDA-and NO-levels in cecum tissue at 15 min, and severity of cecum lesions and adhesions at 1 and 7 d. RESULTS Post-injury, during/after a saline bath, the number of vessels was significantly reduced, the defect was slightly narrowed, bleeding was significant and MDA-levels increased and NO-levels decreased. BPC 157 bath: the vessel presentation was markedly increased, the defect was noticeably narrowed, the bleeding time was shortened and MDA-and NO-levels remained normal. L-NAME: reduced vessel presentation but not more than the control, did not change defect and shortened bleeding. L-arginine: exhibited less vessel reduction, did not change the defect and prolonged bleeding. In combination, mutual counteraction occurred(L-NAME + L-arginine) or the presentation was similar to that of BPC 157 rats(BPC 157 + L-NAME; BPC 157 + L-arginine; BPC 157 + L-NAME + L-arginine), except the defect did not change. Thereby at day 1 and 7, saline, L-NAME, L-arginine and L-NAME + L-arginine failed(defect was still open and large adhesions present). CONCLUSION The therapeutic effect was achieved with BPC 157 alone or in combination with L-NAME and L-arginine as it was able to consolidate the stimulating and inhibiting effects of the NO-system towards more effective healing recruiting vessels.

关键词： BPC 157 perforated cecum L-arginine L-NAME vessels rats

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Pentadecapeptide BPC 157 resolves Pringle maneuver in rats,both ischemia and reperfusion

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World Journal of Hepatology 2020年第5期12卷 184-206页

作者： Marijan Kolovrat Slaven Gojkovic Ivan Krezic Dominik Malekinusic Borna Vrdoljak katarina Kasnik Kovac Tamara Kralj Domagoj Drmic Ivan Barisic katarina horvat pavlov Andreja Petrovic Antonija Duzel Mario Knezevic Ivan Mirkovic Antonio Kokot Alenka Boban Blagaic Sven Seiwerth Predrag Sikiric Departments of Pharmacology and Pathology School of MedicineUniversity of ZagrebZagreb 10000Croatia

BACKGROUND The Pringle maneuver[portal triad obstruction(PTO)]provides huge disturbances during ischemia and even more thereafter in ***,a possible solution may be stable gastric pentadecapeptide BPC 157,with already documented beneficial effects in ischemia/reperfusion ***,BPC 157,as a cytoprotective agent,successfully resolved vessel occlusions in rats(ischemic colitis;deep vein thrombosis,superior anterior pancreaticoduodenal vein;bile duct cirrhosis)through rapid collateral vessel recruitment to circumvent vessel ***,medication BPC 157 regimens were administered as a single challenge before and during ischemia or,alternatively,at various time points during *** To introduce BPC 157 therapy against pringle *** In deeply anesthetised rats,the portal triad was clamped up for 30 *** then underwent reperfusion for either 15 min or 24 ***[(10μg,10 ng/kg)regimens,administered as a single challenge]picked(a)ischemia,PTO period[at 5 min before(ip)or at 5 or 30 min of ligation time(as a bath to PTO)]or(b)reperfusion,post-PTO period[at 1 or 15 min(bath during surgery)or 24 h(ip)reperfusion-time].We provided gross,microscopy,malondialdehyde,serum enzymes,electrocardiogram,portal,caval,and aortal pressure,thrombosis and venography *** BPC 157 counteracts electrocardiogram disturbances(increased P wave amplitude,S1Q3T3 QRS pattern and tachycardia).Rapidly presented vascular pathway(portal vein-superior mesenteric vein-inferior mesenteric vein-rectal veins-left ileal vein-inferior caval vein)as the adequate shunting immediately affected disturbed *** hypertension and severe aortal hypotension during PTO,as well as portal and caval hypertension and mild aortal hypotension in reperfusion and refractory ascites formation were markedly attenuated(during PTO)or completely abrogated(reperfusion);thrombosis in portal vein tributaries and inferior caval vein o

关键词： BPC 157 Pringle maneuver Rats Portal hypertension Caval hypertension Ischemia

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

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World Journal of Gastroenterology 2018年第47期24卷 5366-5378页

作者： Fedor Amic Domagoj Drmic Zdenko Bilic Ivan Krezic Helena Zizek Marina Peklic Robert Klicek Alen Pajtak Enio Amic Tinka Vidovic Mislav Rakic Marija Milkovic Perisa katarina horvat pavlov Antonio Kokot Ante Tvrdeic Alenka Boban Blagaic Mario Zovak Sven Seiwerth Predrag Sikiric Department of Pharmacology Medical Faculty University of Zagreb Department of Pathology Medical Faculty University of Zagreb

AIM To investigate whether duodenal lesions induced by major venous occlusions can be attenuated by BPC 157 regardless nitric oxide(NO) system *** 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 *** 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 *** BPC 157, rapidly bypassing occlusion, rescued the original duodenal flow through IAPDV to SMV flow, aneffect related to the NO system and

关键词： Major venous occlusion Duodenal lesions BPC 157 L-NAME Bypassing L-arginine Reduction of free radical formation Rats

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Bowel adhesion and therapy with the stable gastric pentadecapeptide BPC 157,L-NAME and L-arginine in rats

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World Journal of Gastrointestinal Pharmacology and Therapeutics 2020年第5期11卷 93-109页

作者： Lidija Berkopic Cesar Slaven Gojkovic Ivan Krezic Dominik Malekinusic Helena Zizek Lovorka Batelja Vuletic Andreja Petrovic katarina horvat pavlov Domagoj Drmic Antonio Kokot Josipa Vlainic Sven Seiwerth Predrag Sikiric Department of Pharmacology School of MedicineUniversity of ZagrebZagreb 10000Croatia Department of Pathology School of MedicineUniversity of ZagrebZagreb 10000Croatia Institute Ruder Boskovic Zagreb 10000Croatia

BACKGROUND After parietal peritoneum excision with an underlying superficial layer of muscle tissue in rats,there is failed vasculature,and finally,increased adhesion *** hypothesized that unlike nitric oxide(NO)-agents,L-NAME and/or L-arginine,the application of the stable gastric pentadecapeptide BPC 157 with its most recent vascular effects(“vascular recruitment”)means attenuated bowel adhesion formation and NO-and malondialdehyde(MDA)-tissue *** To focused on the bowel adhesion and the therapy with the BPC 157,its most and application of *** Along with defect creation,medication was(1)during surgery,once,at 1 min after defect creation as an abdominal bath(1 mL/rat),BPC 157(10μg/kg,10 ng/kg,1 mL/rat),an equivolume of saline,L-NAME(5 mg/kg),L-arginine(200 mg/kg)alone and/or ***,medication was(2)intraperitoneally once daily,first application at 30 min after surgery,last application 24 h before assessment at d 7 or d *** a postponed therapy to preexisting adhesion(3),BPC 157(10μg/kg,10 ng/kg intraperitoneally,1 mL/rat)was given once daily since d *** recovery effect of the BPC 157 regimens goes with the presence of abundant vascular vessels in and near the defect,which occurs ***,also applied as post-treatment,BPC 157 creates attenuated adhesions,minimal or no ***,NO-agents have diverse initial and final effects:The initial weakening of blood vessel disappearance and finally,severe worsening of adhesions(LNAME)vs the initial weakening of blood vessel disappearance and finally,attenuation of adhesions formation(L-arginine),which counteract each other response given ***,BPC 157 maintains its beneficial effect also when given with NO-agents(L-NAME+BC 157;L-arginine+BPC 157;L-NAME+L-arginine+BPC 157).Finally,with respect to the increased NO-and MDAvalues-adhesion tissue formation relation,unlike diverse effect of the NO-agents,the BPC 157 application effect regularly

关键词： Abdominal wall defect Adhesions BPC 157 Vascular recruitment Nitric oxide-agents Rats

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Pentadecapeptide BPC 157 resolves suprahepatic occlusion of the inferior caval vein, Budd-Chiari syndrome model in ratsPentadecapeptide BPC 157 resolves suprahepatic occlusion of the inferior caval vein, Budd-Chiari syndrome model in rats

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World Journal of Gastrointestinal Pathophysiology 2020年第1期11卷 1-19页

作者： Slaven Gojkovic Ivan Krezic Borna Vrdoljak Dominik Malekinusic Ivan Barisic andreja Petrovic katarina horvat pavlov Marijan Kolovrat Antonija Duzel Mario Knezevic katarina Kasnik Kovac Domagoj Drmic Lovorka Batelja Vuletic Antonio Kokot Alenka Boban Blagaic Sven Seiwerth Predrag Sikiric Departments of Pharmacology and Pathology Medical Faculty University of ZagrebZagreb 10000Croatia

BACKGROUND Recently,as a possible therapy resolving solution,pentadecapeptide BPC 157 therapy,has been used in alleviating various vascular occlusion *** 157 was previously reviewed as novel mediator of Robert cytoprotection and endothelium protection in the stomach,and gut-brain axis,beneficial therapy in gastrointestinal tract,with particular reference to vascular recruitment,ulcerative colitis and tumor cachexia,and other tissues *** we raised new hypothesis about BPC 157 therapy in the Budd-Chiari syndrome in rats,rapid bypassing of the suprahepatic inferior caval vein occlusion,and rats recovery with the active and effective pharmacotherapy *** To investigate Budd-Chiari syndrome model(inferior caval vein suprahepatic occlusion)resolution,since BPC 157 resolves various rat vascular *** We assessed the activated bypassing pathways between the inferior and superior caval veins and portocaval shunt,counteracted caval/portal hypertension,aortal hypotension,venous/arterial thrombosis,electrocardiogram disturbances,liver and gastrointestinal lesions(i.e.,stomach and duodenum hemorrhages,in particular,congestion).Rats with suprahepatic occlusion of the inferior vena cava by ligation were medicated at 1 min,15 min,24 h,or 48 h *** consisted of 10μg/kg BPC 157,10 ng BPC 157 or 5 m L/kg saline,administered once as an abdominal bath or intragastric *** and microscopic observations were made,in addition to assessments of electrical activity of the heart(electrocardiogram),portal and caval hypertension,aortal hypotension,thrombosis,hepatomegaly,splenomegaly and ***,levels of nitric oxide,malondialdehyde in the liver and serum enzymes were *** BPC 157 counteracted increased P wave amplitude,tachycardia and ST-elevation,i.e.,right heart failure from acute thrombotic coronary *** bypassing pathway of the inferior vena cava-azygos(hemiazygos)vein-superior

关键词： BPC 157 Budd Chiari syndrome Portal/caval hypertension

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