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Endogenous D-serine is involved in induction of neuronal death by N-methyl-D-aspartate and simulated ischemia in rat cerebrocortical slices.

Abstract
Emerging evidence indicates that D-serine rather than glycine serves as an endogenous agonist at glycine site of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors, in several nervous tissues, including the developing cerebellum and the retina. Here, we examined whether endogenous D-serine plays a significant role in neuronal damage resulting from excitotoxic insults in the cerebral cortex, using rat brain slices maintained in a defined salt solution. Neuronal cell death induced by application of NMDA or by oxygen-glucose deprivation (simulated ischemia) was markedly suppressed by a competitive glycine site antagonist 2,7-dichlorokynurenic acid. Addition of glycine or D-serine did not augment neuronal damage by NMDA or simulated ischemia, indicating that sufficient amount of glycine site agonist(s) is supplied endogenously within the slices. Application of D-amino acid oxidase, an enzyme that degrades D-serine, markedly inhibited neuronal damage by NMDA and simulated ischemia, which was reversed by addition of excess D-serine or glycine. Sensitivity to the glycine site antagonist of NMDA- or ischemia-induced damage was not affected by the presence of a non-NMDA receptor antagonist, suggesting that kainate receptor-stimulated D-serine release as demonstrated in primary cultured astrocytes does not contribute significantly to the extent of neuronal injury in these settings. The present results suggest that endogenous supply of D-serine as a glycine site agonist is important for neuronal injury involving NMDA receptor overactivation in the cerebral cortex.
AuthorsHiroshi Katsuki, Miki Nonaka, Hisashi Shirakawa, Toshiaki Kume, Akinori Akaike
JournalThe Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 311 Issue 2 Pg. 836-44 (Nov 2004) ISSN: 0022-3565 [Print] United States
PMID15240826 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Excitatory Amino Acid Agonists
  • Serine
  • N-Methylaspartate
Topics
  • Animals
  • Cell Death (drug effects)
  • Cerebral Cortex (pathology)
  • Excitatory Amino Acid Agonists (pharmacology)
  • Female
  • In Vitro Techniques
  • Ischemia (pathology)
  • Male
  • N-Methylaspartate (pharmacology)
  • Neurons (cytology, drug effects)
  • Rats
  • Rats, Wistar
  • Serine (physiology)

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