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

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.