N-methyl-d-aspartate receptor antagonist therapy suppresses colon motility and inflammatory activation six days after the onset of experimental colitis in rats

Dániel Érces, Gabriella Varga, Borbála Fazekas, Tamás Kovács, Tünde Tkés, László Tiszlavicz, Ferenc Fülöp, László Vécsei, Mihály Boros, József Kaszaki

Research output: Article

24 Citations (Scopus)

Abstract

We set out to investigate the time-dependent colon motility and inflammatory changes in a rodent model of 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis in order to estimate the efficacy of N-methyl-d-aspartate (NMDA) receptor antagonist therapy administered 6 day after the acute inflammatory event. Anaesthetized Sprague-Dawley rats were randomized to control (n=6) or colitis groups (n=18). The endogenous NMDA receptor antagonist kynurenic acid (n=6) or the synthetic analog SZR-72 (n=6) was administered 6 day after TNBS induction. Large bowel motility parameters, macrohaemodynamics and serosal microcirculatory changes were recorded; the severity of colonic damage was monitored by using in vivo confocal laser endomicroscopy. Nitrite/nitrate and nitrotyrosine levels, and xanthine oxidoreductase and myeloperoxidase activities were determined on colon biopsies; plasma levels of TNF-α and IL-6 were compared with those under control and 1-day colitis (n=6) conditions. TNBS induction elevated the tissue inflammatory enzyme activities, proinflammatory cytokine release, and nitrite/nitrate and nitrotyrosine formation. The microscopic vascular and mucosal lesions were accompanied by significant increases in serosal microcirculation and frequent intestinal movements 6 day after colitis. The NMDA receptor antagonist treatments significantly decreased the signs of inflammatory activation and the levels of nitric oxide end-products, normalized the microcirculation and the rate of bowel movements in both NMDA receptor antagonist-treated colitis groups. Blockade of the enteric NMDA receptors 6 day after colitis induction concurrently influenced NO production-linked nitrosative stress and colon dysmotility and may therefore offer a possibility via which to inhibit the progression of inflammatory changes in the later phase of TNBS colitis.

Original languageEnglish
Pages (from-to)225-234
Number of pages10
JournalEuropean Journal of Pharmacology
Volume691
Issue number1-3
DOIs
Publication statusPublished - szept. 15 2012

ASJC Scopus subject areas

  • Pharmacology

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