EFFECT OF SA4503, A NOVEL SIGMA(1) RECEPTOR AGONIST, AGAINST GLUTAMATE NEUROTOXICITY IN CULTURED RAT RETINAL NEURONS

We examined the effects of sigma(1) receptor agonists against glutamat e-induced neurotoxicity in cultured retinal neurons. Primary cultures obtained from fetal rat retinas (16-19 d gestation) were used. The neu rotoxic effect of glutamate was quantitatively assessed using the tryp an blue exclusion method. A brief exposure of retinal cultures to glut amate (500 mu M) led to delayed neuronal cell death. The glutamate-ind uced neurotoxicity was inhibited by 11-dihydro-5H-dibenzo-[a,b]-cycloh epten-5,10-imine hydrogen maleate (MK-801). The sigma(1) receptor agon ists, -dimethoxyphenethyl)-4-(3-phenylpropyl)-piperazine dihydrochlori de (SA4503) and(+)-pentazocine at a concentration range of 0.1 similar to 100 mu M reduced the glutamate-induced neurotoxicity in a dose-dep endent manner. In addition, the neuroprotective effects of both SA4503 and (+)-pentazocine were antagonized by co-treatment with N, l-2-[4-m ethoxy-3-(2-phenylethoxy)phenyl]ethylamine monohydrochloride (NE-100), a putative sigma(1) receptor antagonist. These findings suggest that sigma(1) receptor agonists protect retinal cells against glutamate-ind uced neurotoxicity. (C) 1998 Elsevier Science B.V.