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

AbstractBACKGROUND:
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-alpha), 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.
AuthorsG Varga, D Erces, B Fazekas, M Fülöp, T Kovács, J Kaszaki, F Fülöp, L Vécsei, M Boros
JournalNeurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society (Neurogastroenterol Motil) Vol. 22 Issue 2 Pg. 217-25, e68 (Feb 2010) ISSN: 1365-2982 [Electronic] England
PMID19735360 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Excitatory Amino Acid Antagonists
  • Receptors, N-Methyl-D-Aspartate
  • SZR 72
  • Tumor Necrosis Factor-alpha
  • Trinitrobenzenesulfonic Acid
  • Peroxidase
  • Nitric Oxide Synthase
  • Xanthine Oxidase
  • Kynurenic Acid
Topics
  • Analysis of Variance
  • Animals
  • Blood Pressure (drug effects, physiology)
  • Colitis (chemically induced, metabolism, physiopathology)
  • Colon (drug effects, metabolism, physiopathology)
  • Disease Models, Animal
  • Excitatory Amino Acid Antagonists (pharmacology)
  • Gastrointestinal Motility (drug effects, physiology)
  • Inflammation (metabolism, physiopathology)
  • Kynurenic Acid (analogs & derivatives, pharmacology)
  • Male
  • Nitric Oxide Synthase (metabolism)
  • Peroxidase (metabolism)
  • Random Allocation
  • Rats
  • Rats, Wistar
  • Receptors, N-Methyl-D-Aspartate (metabolism)
  • Time Factors
  • Trinitrobenzenesulfonic Acid (toxicity)
  • Tumor Necrosis Factor-alpha (blood)
  • Xanthine Oxidase (metabolism)

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