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Purpose: To examine the effects of ifenprodil on glutamate-induced neurotoxicity in cultured retinal neurons., Methods: Primary cultures obtained from the fetal rat retina (gestation day 17-19) were used for the experiment. Neurotoxicity effects on retinal cultures were quantitatively assessed by the trypan blue exclusion method. The cells were exposed briefly (10 min) to excitatory amino acids (EAA, 1 mM) and then were incubated for 1 h in an EAA-free medium. Ifenprodil (10 mM) was added for the 10-min exposure to EAA and the subsequent 60-min incubation in an EAA-free medium., Results: Ifenprodil dose-dependently prevented cell death induced by glutamate or NMDA, but did not affect that induced by kainate. The protective effects of ifenprodil against glutamate neurotoxicity were significantly reduced by spermidine, a polyamine modulatory site agonist, but not by glycine, a strychnine-insensitive glycine site agonist., Conclusion: The findings suggest that ifenprodil protected the cultured retinal cells we used in this study against glutamate neurotoxicity by its inhibitory action on the polyamine modulatory site of the NMDA receptor.