Basic Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Aug 7, 2017; 23(29): 5304-5312
Published online Aug 7, 2017. doi: 10.3748/wjg.v23.i29.5304
Celecoxib-induced gastrointestinal, liver and brain lesions in rats, counteraction by BPC 157 or L-arginine, aggravation by L-NAME
Domagoj Drmic, Danijela Kolenc, Spomenko Ilic, Lara Bauk, Marko Sever, Anita Zenko Sever, Kresimir Luetic, Jelena Suran, Sven Seiwerth, Predrag Sikiric
Domagoj Drmic, Danijela Kolenc, Spomenko Ilic, Lara Bauk, Marko Sever, Anita Zenko Sever, Kresimir Luetic, Jelena Suran, Sven Seiwerth, Predrag Sikiric, Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Salata, 10000 Zagreb, Croatia
Domagoj Drmic, Danijela Kolenc, Spomenko Ilic, Lara Bauk, Marko Sever, Anita Zenko Sever, Kresimir Luetic, Jelena Suran, Sven Seiwerth, Predrag Sikiric, Faculty of Medicine, J.J. Strossmayer University of Osijek, 31000 Osijek, Croatia
Author contributions: Drmic D, Kolenc D, Ilic S, Suran J, Seiwerth S and Sikiric P designed the research; Drmic D, Kolenc D, Ilic S, Bauk L, Sever M, Zenko Sever A, Seiwerth S and Sikiric P performed the research; Seiwerth S and Sikiric P contributed reagents and analytic tools. Drmic D, Kolenc D, Ilic S, Bauk L, Sever M, Zenko Sever A, Luetic K, Suran J, Seiwerth S and Sikiric P analyzed the data; Drmic D, Kolenc D, Seiwerth S and Sikiric P wrote the paper.
Institutional review board statement: The study was reviewed and approved by the Department of Veterinary, Ministry of Agriculture, Croatia, No. UP/I 322-01/07-01/210.
Conflict-of-interest statement: The authors state that they have no conflicts of interest.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (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/
Correspondence to: Predrag Sikiric, MD, PhD, Professor, Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Salata 11, POB 916, 10000 Zagreb, Croatia. sikiric@mef.hr
Telephone: +385-1-4566833 Fax: +385-1-4920050
Received: February 15, 2017
Peer-review started: February 19, 2017
First decision: April 5, 2017
Revised: May 3, 2017
Accepted: July 4, 2017
Article in press: July 4, 2017
Published online: August 7, 2017
Processing time: 172 Days and 18.2 Hours
Abstract
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.

Keywords: BPC 157; Celecoxib; L-arginine; N(G)-nitro-L-arginine methyl ester; Rats

Core tip: In rats treated with the COX-2 inhibitor celecoxib, BPC 157 (given intraperitoneally) counteracted lesion development in the stomach, liver and brain. BPC 157 treatment alongside with N(G)-nitro-L-arginine methyl ester (L-NAME) also attenuated any effect of L-NAME that would otherwise have intensified the deleterious regular course. Consistently, with exacerbation (induced by L-NAME administration) and amelioration (due to L-arginine) of gastric, liver and brain lesions, L-arginine amelioration prevailed (i.e., the gastric, liver and brain lesions were attenuated) when given together with L-NAME (L-NAME + L-arginine), an effect further reversed toward a marked beneficial effect by the addition of BPC 157 (L-NAME + L-arginine + BPC 157).