7‐Chlorokynurenate Blocks NMDA Receptor‐Mediated Neurotoxicity in Murine Cortical Culture

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Abstract
We examined the neuroprotective actions of the glycine site N-methyl-D-aspartate (NMDA) antagonist, 7-chlorokynurenate, in murine neocortical cell cultures. Cultures exposed for 5 min to 100–500 μM NMDA in the absence of added glycine developed substantial neuronal degeneration over the next 24 h. The addition of 10 μM glycine did not increase submaximal NMDA-induced neuronal injury, suggesting that endogenous glycine levels were sufficient to saturate its receptor sites on NMDA receptor complexes. Addition of 3–300 μM 7-chlorokynurenate produced concentration-dependent reduction in this neuronal damage with an IC50 of approximately 30 μM. Some injury reduction was seen even if the drug was added after completion of the NMDA exposure. The protective effect of 100 μM 7-chlorokynurenate could be overcome by adding 10–1000 μM glycine (glycine median effective concentration (EC50) approximately 100 μM) or 1 mM D-serine. As predicted by its ability to block NMDA receptor-mediated injury, 10–300 μM 7-chlorokynurenate also produced concentration-dependent reduction in the neuronal loss induced by 50–60 min exposure to combined glucose and oxygen deprivation. These data support the suggestion that pharmacologic interference with the binding of glycine to the NMDA receptor complex represents a potentially effective approach to blocking NMDA receptor-induced neurotoxicity in ischemia.