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.
Footnotes
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This study was supported in part by a grant-in-aid for scientific research from The Ministry of Education, Culture, Sports, Science and Technology, Japan, and from the Japan Society for the Promotion of Science. H.S. is supported as a teaching assistant by the 21st Century Center of Excellence Program “Knowledge Information Infrastructure for Genome Science”.
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doi:10.1124/jpet.104.070912.
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ABBREVIATIONS: NMDA, N-methyl-d-aspartate; DAAOX, d-amino acid oxidase; MK-801, (-)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate; NBQX, 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline; DCKA, 2,7-dichlorokynurenic acid; AIB, α-aminoisobutyric acid; PBS, phosphate-buffered saline.
- Received May 2, 2004.
- Accepted July 7, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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