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Research ArticleNEUROPHARMACOLOGY

Endogenous d-Serine Is Involved in Induction of Neuronal Death by N-Methyl-d-aspartate and Simulated Ischemia in Rat Cerebrocortical Slices

Hiroshi Katsuki, Miki Nonaka, Hisashi Shirakawa, Toshiaki Kume and Akinori Akaike
Journal of Pharmacology and Experimental Therapeutics November 2004, 311 (2) 836-844; DOI: https://doi.org/10.1124/jpet.104.070912
Hiroshi Katsuki
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Miki Nonaka
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Hisashi Shirakawa
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Toshiaki Kume
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Akinori Akaike
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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

  • 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”.

  • doi:10.1124/jpet.104.070912.

  • 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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Journal of Pharmacology and Experimental Therapeutics: 311 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 311, Issue 2
1 Nov 2004
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Research ArticleNEUROPHARMACOLOGY

Endogenous d-Serine Is Involved in Induction of Neuronal Death by N-Methyl-d-aspartate and Simulated Ischemia in Rat Cerebrocortical Slices

Hiroshi Katsuki, Miki Nonaka, Hisashi Shirakawa, Toshiaki Kume and Akinori Akaike
Journal of Pharmacology and Experimental Therapeutics November 1, 2004, 311 (2) 836-844; DOI: https://doi.org/10.1124/jpet.104.070912

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Research ArticleNEUROPHARMACOLOGY

Endogenous d-Serine Is Involved in Induction of Neuronal Death by N-Methyl-d-aspartate and Simulated Ischemia in Rat Cerebrocortical Slices

Hiroshi Katsuki, Miki Nonaka, Hisashi Shirakawa, Toshiaki Kume and Akinori Akaike
Journal of Pharmacology and Experimental Therapeutics November 1, 2004, 311 (2) 836-844; DOI: https://doi.org/10.1124/jpet.104.070912
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