Role of Glycine in the N‐Methyl‐d‐Aspartate‐Mediated Neuronal Cytotoxicity

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Abstract
Current evidence indicates that glutamate acting via the N‐methyl‐d‐aspartate (NMDA) receptor/ion channel complex plays a major role in the neuronal degeneration associated with a variety of neurological disorders. In this report the role of glycine in NMDA neurotoxicity was examined. We demonstrate that NMDA‐mediated neurotoxicity is markedly potentiated by glycine and other amino acids, e.g., d‐serine. Putative glycine antagonists HA‐966 and 7‐chlorokynurenic acid were highly effective in preventing NMDA neurotoxicity, even in the absence of added glycine. The neuroprotective action of HA‐966 and 7‐chlorokynurenic acid, but not that of NMDA antagonists 3‐(2‐carboxypiperazine‐4‐yl)propylphosphonate and MK‐801, could be reversed by glycine. These results indicate that glycine, operating through a strychnine‐insensitive glycine site, plays a central permissive role in NMDA‐mediated neurotoxicity.

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