N-methyl-D-aspartate receptor antagonist therapy suppresses colon motility and inflammatory activation six days after the onset of experimental colitis in rats.
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.
Institute of Surgical Research, Faculty of Medicine, University of Szeged, Hungary.
Dániel
D
Érces
Gabriella
G
Varga
Borbála
B
Fazekas
Tamás
T
Kovács
Tünde
T
Tőkés
László
L
Tiszlavicz
Ferenc
F
Fülöp
László
L
Vécsei
Mihály
M
Boros
József
J
Kaszaki
D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D003106:Colon / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D005769:Gastrointestinal Motility / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects; D015850:Interleukin-6 / Q000097:blood; D007736:Kynurenic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D014968:Xanthine Dehydrogenase / Q000378:metabolism
D015850:Interleukin-6; D016194:Receptors, N-Methyl-D-Aspartate; C533052:SZR 72; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D009195:Peroxidase; D014968:Xanthine Dehydrogenase; D007736:Kynurenic Acid