Action of the anti-ischemic agent ifenprodil on N-methyl-D-aspartate and kainate-mediated excitotoxicity.

The efficacy of ifenprodil to antagonize N-methyl-D-aspartate (NMDA) and kainate (KA)-induced acute excitotoxicity was evaluated in embryonic day 13 chick retina. Incubation with either 50 microM NMDA or KA produced a characteristic histological lesion and release of endogenous gamma-aminobutyric acid (GABA). Ifenprodil potently attenuated NMDA-induced GABA efflux by 80% (IC50, 1.26 microM). Histology showed protection of all but a subpopulation of amacrine neurons and processes even at 500 microM ifenprodil. MK-801 and CGS 19755, uncompetitive and competitive NMDA antagonists, respectively, protected all NMDA-sensitive amacrines, including the ifenprodil-resistant population, whilst CNQX, a non-NMDA glutamate receptor antagonist, was ineffective. Ifenprodil was less effective versus KA, requiring 10-100-fold higher concentrations to significantly attenuate GABA release. The potent antagonism of NMDA-mediated acute excitotoxicity by ifenprodil may explain its efficacy as an anti-ischemic agent. Ifenprodil does, however, leave unprotected a subpopulation of NMDA-susceptible neurons suggesting a heterogeneity in the NMDA receptor population.