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Underlying mechanism for NMDA receptor antagonism by the anti-inflammatory drug, sulfasalazine, in mouse cortical neurons.

Authors
Noh, JH; Gwag, BJ; Chung, JM
Citation
Neuropharmacology, 50(1):1-15, 2006
Journal Title
Neuropharmacology
ISSN
0028-39081873-7064
Abstract
Sulfasalazine (SULFA), of anti-inflammatory drugs, shows a protective action against NMDA-induced neuronal toxicity. Here, we used an electrophysiological study of the pharmacological effects of SULFA on NMDA receptors to examine the molecular mechanisms underlying the neuroprotective role of SULFA. The drug acted as a typical noncompetitive inhibitor with neither agonist- nor use-dependency, and antagonized NMDA-evoked responses in a voltage-independent manner, suggesting that SULFA is not an open channel blocker. Noise and single channel analyses showed that SULFA-blocked NMDA responses by reducing the number of NMDA channels available for activation, and also reduced the channel open probability without changing single channel conductance. Moreover, SULFA accelerated NMDA desensitization without affecting the affinity of the receptor for NMDA or glutamate. Taken together, these data indicate that SULFA blocks the NMDA response by reducing the number of NMDA channels available for activation. This appears to occur via a SULFA-induced decrease in the channel open probability, and a concomitant acceleration of the desensitization response, which is likely associated with a reduced affinity for glycine. SULFA indeed decreased the glycine-potentiated NMDA response without binding directly to the glycine site. Our results suggest that SULFA acts as a noncompetitive NMDA receptor antagonist with an allosteric glycine modulation.
MeSH terms
AlgorithmsAnimalsAnti-Inflammatory Agents, Non-Steroidal/pharmacology*Cells, CulturedCerebral Cortex/cytology*Cerebral Cortex/drug effectsDose-Response Relationship, DrugElectrophysiologyGlycine/metabolismKineticsMembrane Potentials/drug effectsMiceMice, Inbred ICRNeurons/drug effects*Patch-Clamp TechniquesReceptors, N-Methyl-D-Aspartate/antagonists & inhibitors*Sulfasalazine/pharmacology*
DOI
10.1016/j.neuropharm.2005.07.020
PMID
16169564
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Pharmacology
AJOU Authors
곽, 병주
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