Basic Study
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Pathophysiol. Mar 13, 2020; 11(1): 1-19
Published online Mar 13, 2020. doi: 10.4291/wjgp.v11.i1.1
Pentadecapeptide BPC 157 resolves suprahepatic occlusion of the inferior caval vein, Budd-Chiari syndrome model in rats
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
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 Zagreb, Zagreb 10000, Croatia
Author contributions: Gojkovic S, Krezic I, Vrdoljak B, Malekinusic D, Barisic I, Petrovic A, Horvat Pavlov K, Kolovrat M, Duzel A, Knezevic M, Kasnik Kovac K, Drmic D, Batelja Vuletic L, Kokot A, Boban Blagaic A, Seiwerth S and Sikiric P performed experiments; Gojkovic S, Krezic I, Vrdoljak B, Malekinusic D, Barisic I, Petrovic A, Horvat Pavlov K, Kolovrat M, Duzel A, Knezevic M, Kasnik Kovac K, Drmic D, Batelja Vuletic L, Kokot A, Boban Blagaic A, Seiwerth S and Sikiric P analysed data; Seiwerth S and Sikiric P contributed reagents and analytic tools; Gojkovic S, Drmic D, Seiwerth S and Sikiric P wrote the manuscript.
Institutional review board statement: The study was reviewed and approved by the Department of Veterinary, Ministry of Agriculture, Republic of Croatia, No: UP/I 322-01/07-01/210.
Institutional animal care and use committee statement: Male Albino Wistar, body weight 200 g, 12 weeks old, randomly assigned, used in all of the experiments, 6 rats/group/interval, approved by local Ethic Committee.
Conflict-of-interest statement: The authors state that they have no conflicts of interest.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Predrag Sikiric, MD, PhD, Professor, Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, POB 916, Zagreb 10000, Croatia. sikiric@mef.hr
Received: October 7, 2019
Peer-review started: October 7, 2019
First decision: November 27, 2019
Revised: December 20, 2019
Accepted: January 19, 2020
Article in press: January 19, 2020
Published online: March 13, 2020
Processing time: 157 Days and 14 Hours
Abstract
BACKGROUND

Recently, as a possible therapy resolving solution, pentadecapeptide BPC 157 therapy, has been used in alleviating various vascular occlusion disturbances. BPC 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 healing. Here 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 treatment.

AIM

To investigate Budd-Chiari syndrome model (inferior caval vein suprahepatic occlusion) resolution, since BPC 157 resolves various rat vascular occlusion.

METHODS

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 post-ligation. Medication consisted of 10 µg/kg BPC 157, 10 ng BPC 157 or 5 mL/kg saline, administered once as an abdominal bath or intragastric application. Gross 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 venography. Furthermore, levels of nitric oxide, malondialdehyde in the liver and serum enzymes were determined.

RESULTS

BPC 157 counteracted increased P wave amplitude, tachycardia and ST-elevation, i.e., right heart failure from acute thrombotic coronary occlusion. The bypassing pathway of the inferior vena cava-azygos (hemiazygos) vein-superior vena cava and portocaval shunt occurred rapidly. Even with severe caval ˃ portal hypertension, BPC 157 antagonized portal and caval hypertension and aortal hypotension, and also reduced refractory ascites. Thrombosis of portal vein tributaries, inferior vena cava, and hepatic and coronary arteries was attenuated. In addition, there was reduced pathology of the lungs (severe capillary congestion) and liver (dilated central veins and terminal portal venules), decreased intestine hemorrhagic lesions (substantial capillary congestion, submucosal edema and architecture loss), and increased liver and spleen weight. During the period of ligation, nitric oxide- and malondialdehyde-levels in the liver remained within normal healthy values, and increases in serum enzymes were markedly reduced.

CONCLUSION

BPC 157 counteracts Budd Chiari syndrome in rats.

Keywords: BPC 157; Budd Chiari syndrome; Portal/caval hypertension

Core tip: To demonstrate that pentadecapeptide BPC 157 can resolve Budd Chiari syndrome in rats, we provided gross, microscopy, nitric oxide-, malondialdehyde-liver levels, serum enzymes, electrocardiogram, portal, caval hypertension, aortal hypotension, thrombosis, hepatomegaly, splenomegaly and venography assessments. BPC 157 counteracts increased P wave amplitude, tachycardia and ST-elevation (i.e., right heart failure; acute thrombotic coronary occlusion). Bypassing pathway (inferior caval vein-azygos (hemiazygos) vein-superior caval vein and portocaval shunt) rapidly appears. Even with the severe caval ˃ portal hypertension, BPC 157 counteracts portal and caval hypertension and aortal hypotension. BPC 157 counteracts refractory ascites. Portal vein tributaries, inferior caval vein, hepatic and coronary arteries thrombosis was counteracted. In addition, there are counteracted severe lung pathology, liver, intestine hemorrhagic lesion, increased liver and spleen weight. During ligation-period, nitric oxide- and malondialdehyde-level in liver remained within normal healthy values, and increased serum enzymes markedly lessened. In conclusion, BPC 157 counteracts Budd Chiari syndrome in rats.