N-METHYL-D-ASPARTATE-MEDIATED OR GLUTAMATE-MEDIATED TOXICITY IN CULTURED RAT CORTICAL-NEURONS IS ANTAGONIZED BY FPL-15896AR

The neuroprotective action of (S)-alpha-phenyl-2-pyridineethanamine di hydrochloride (FPL 15896AR), a novel noncompetitive N-methyl-D-asparta te (NMDA) receptor antagonist, was examined in primary rat cortical ne uronal cultures. Exposure of cortical cultures to NMDA (50 mu M) or gl utamate (50 mu M) for 15 min resulted in the death of 85-95% of the ne urons during the next 24 h. This neurotoxicity was completely eliminat ed by adding FPL 15896AR (50 mu M) to the cultures during the time of NMDA or glutamate exposure. Neuroprotective concentrations of FPL 1589 6AR also inhibited other acute effects of NMDA, FPL 15896AR (50 mu M) prevented the loss of membrane-associated protein kinase C activity th at developed by 4 h after transient exposure to 50 mu M NMDA or 50 mu M glutamate. FPL 15896AR also reduced by similar to 35% the magnitude of NMDA-triggered increases in intracellular free Ca2+ concentration i n the cortical cultures. These data indicate that NMDA-mediated toxici ty in cultured cortical neurons can be blocked by the NMDA antagonist FPL 15896AR.