TY - JOUR T1 - Endogenous <span class="sc">d</span>-Serine Is Involved in Induction of Neuronal Death by <em>N</em>-Methyl-<span class="sc">d</span>-aspartate and Simulated Ischemia in Rat Cerebrocortical Slices JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 836 LP - 844 DO - 10.1124/jpet.104.070912 VL - 311 IS - 2 AU - Hiroshi Katsuki AU - Miki Nonaka AU - Hisashi Shirakawa AU - Toshiaki Kume AU - Akinori Akaike Y1 - 2004/11/01 UR - http://jpet.aspetjournals.org/content/311/2/836.abstract N2 - 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. The American Society for Pharmacology and Experimental Therapeutics ER -