Aspartate neurotoxicity on cultured cortical neurons

L-aspartate neurotoxicity was quantitatively characterized in murine cortical cell cultures. Five-minute exposure to 30 microM-3 mM L-aspartate resulted in concentration-dependent (ED50 about 190 microM) neuronal destruction over the next 10 hr; glia were not injured. D-aspartate and L-aspartate were roughly equipotent neurotoxins. Ion substitution experiments suggested that L-aspartate neurotoxicity is comprised of both acute, sodium-dependent "excitotoxicity" and delayed, calcium-dependent degeneration, with the latter predominant under conditions of brief exposure. Aspartate neurotoxicity could be attenuated by D-2-amino-5-phosphonovalerate (D-APV), dextrorphan, ketamine, and kynurenate, but not by L-glutamate diethyl ester or gamma-D-glutamylaminomethyl sulfonate, consistent with principal involvement of N-methyl-D-aspartate receptors. D-APV and dextrorphan produced different effects on the aspartate concentration-toxicity relation; the former drug was consistent with a competitive and the latter with a noncompetitive mechanism of antagonism.