Contribution of endogenous glycine and d-serine to excitotoxic and ischemic cell death in rat cerebrocortical slice cultures.
N-methyl-D-aspartate (NMDA) receptors, whose activation requires glycine site stimulation, play crucial roles in various physiological and pathological conditions in the brain. We investigated the regulatory roles of potential endogenous glycine site agonists, glycine and d-serine, in excitotoxic and ischemic cell death in the cerebral cortex. Cytotoxicity of NMDA on rat cerebrocortical slice cultures was potentiated by addition of glycine or d-serine. In contrast, cell death induced by oxygen/glucose deprivation (OGD) was not affected by exogenous glycine or d-serine, although blockade of NMDA receptors by MK-801 abolished cell death. In addition, higher concentrations of 2,7-dichlorokynurenic acid (DCKA), a competitive glycine site antagonist, were required to suppress OGD-induced cell death than those to suppress NMDA cytotoxicity. We also found that OGD triggered a robust increase in extracellular glycine. A glycine transporter blocker ALX 5407 increased the extracellular level of glycine, and the protective effect of DCKA against NMDA cytotoxicity was diminished in the presence of ALX 5407. Sensitivity of NMDA cytotoxicity to DCKA was also diminished by l-serine that increased the extracellular level of d-serine. These results indicate that both glycine and d-serine can act as endogenous ligands for NMDA receptor glycine site in the cerebral cortex, and that endogenous glycine may saturate the glycine site under ischemic conditions. The present findings are important for the interpretation of the mechanisms of NMDA and OGD cytotoxicity.
Katsuki
Hiroshi
H
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Watanabe
Yoshinori
Y
Fujimoto
Shinji
S
Kume
Toshiaki
T
Akaike
Akinori
A
D000818:Animals; D000831:Animals, Newborn; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D005998:Glycine / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D066298:In Vitro Techniques; D007511:Ischemia / Q000378:metabolism / Q000473:pathology; D016202:N-Methylaspartate / Q000494:pharmacology; D010100:Oxygen / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012694:Serine / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*
D018690:Excitatory Amino Acid Agonists; D016194:Receptors, N-Methyl-D-Aspartate; D012694:Serine; D016202:N-Methylaspartate; D005947:Glucose; D010100:Oxygen; D005998:Glycine