N-Methyl-d-aspartate receptor antagonism decreases motility and inflammatory activation in the early phase of acute experimental colitis in the rat

摘要

Background Inflammatory bowel diseases are accompanied by severe motility disorders. The aim of our study was to investigate whether the blockade of peripheral N-methyl-D-aspartate (NMDA)-sensitive glutamate receptors (NMDA-Rs) alters motility changes in chemically induced acute colitis and how this modulation is accomplished. Methods The inflammatory and motility changes in 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis were studied in anaesthetized Wistar rats following treatment with the natural NMDA-R antagonist kynurenic acid (KynA) or SZR-72, a blood-brain barrier-permeable synthetic KynA analogue. The macrohaemodynamics, serosal microcirculation (visualized by intravital videomicroscopy), plasma levels of tumour necrosis factor alpha (TNF-α), inflammatory enzyme activities (xanthine oxidoreductase (XOR), myeloperoxidase (MPO) and nitric oxide synthase (NOS)), and colonic motility (with a strain-gauge technique) were evaluated 17 h after colitis induction and compared with the control conditions. Key Results The TNBS enema induced a systemic hyperdynamic circulatory reaction, increased the serosal capillary blood flow, significantly elevated the mucosal XOR, MPO and NOS activities and augmented the colonic motility relative to the controls. The NMDA-R antagonist treatment with KynA or SZR-72 significantly reduced the XOR, NOS and MPO activities, decreased the motility and increased the tone of the colon. Conclusions & Inferences These data demonstrate a potential modulatory mechanism of NMDA-R in altered colonic motility in TNBS colitis. Inhibition of the enteric NMDA-Rs may provide a therapeutic option via which to influence intestinal hypermotility, microcirculatory changes and inflammatory activation simultaneously.