Protection by eliprodil against excitotoxicity in cultured rat retinal ganglion cells

PURPOSE. TO test whether eliprodil (SL 82.0715), a unique antagonist for th e N-methyl-D-aspartate (NMDA) receptor, is protective in the glutamate-indu ced cytotoxicity model in cultured rat retinal ganglion cells (RGCs). METHODS. TWO to four days after a fluorescent dye, Di-I, was injected near the superior colliculi, neonatal rats were killed, and retinal cells were d issociated and cultured. Survival of RGCs after drug treatment was assayed by counting Di-I fluorescent cells. RESULTS. In rat RGCs, glutamate-induced toxicity with a mean EC50 of 10.7 m u M. Only 47% of RGCs survived after a 3-day treatment with 100 mu M glutam ate. Studies using selective agonists and antagonists indicated that the gl utamate-induced toxicity was mediated largely by the NMDA receptor. Pretrea tment with eliprodil protected against such toxicity. Eliprodil exhibited a mean IC50 of 1.0 nM (log [IC50] = -9.00 +/- 0.01, mean +/- SEM, n = 3; aga inst cell death produced by 100 mu M glutamate). At 1 mu M, eliprodil was m aximally protective; cell survival in the presence of 100 I-LM glutamate ch allenge was 100% +/- 5% (n = 3). This protective effect of eliprodil may be related to its reduction (by 78%) of NMDA-induced currents recorded under patch-clamp recording in these cells. CONCLUSIONS. Eliprodil is protective against glutamate cytotoxicity in reti nal neurons. It may be a useful novel compound for the treatment of retinop athies including glaucoma in which excitotoxicity has been implicated.