PROSTAGLANDIN E(2) PROTECTS CULTURED CORTICAL-NEURONS AGAINST N-METHYL-D-ASPARTATE RECEPTOR-MEDIATED GLUTAMATE CYTOTOXICITY

The effects of prostaglandin (PG) E(2) on glutamate-induced cytotoxicity were examined using primary cultures of rat cortical neurons. The cell viability was significantly reduced when cultures were briefly exposed to either glutamate or N-methyl-D-aspartate (NMDA) then incubated with normal medium for 1 h. Similar cytotoxicity was observed with the brief application of ionomycin, a calcium ionophore, and S-nitrosocysteine, a nitric oxide (NO)-generating agent. PGE(2) at concentrations of 0.01-1 mu M dose-dependently ameliorated the glutamate-induced cytotoxicity. PGE(1), butaprost, an EP(2) receptor agonist, and 8-bromo-cAMP were also effective in protecting cultures against glutamate cytotoxicity. By contrast, neither 17-phenpl-omega-trinor-PGE(2), an EP(1) receptor agonist, nor M&B 28767, an EP(3) receptor agonist, affected glutamate-induced cytotoxicity. NMDA-induced cytotoxicity was ameliorated by PGE(2), butaprost, MK-801, N-omega-nitro-L-arginine, a NO synthase inhibitor, and hemoglobin, which binds NO. These agents excluding MK-801 ameliorated the ionomycin-induced cytotoxicity. The cytotoxicity induced by S-nitrosocysteine was prevented only by hemoglobin but not by the other agents including PGE(2). These findings indicate that PGE(2) protects cultured cortical neurons against NMDA receptor-mediated glutamate neurotoxicity via EP(2) receptors. EP(2) receptor stimulation may suppress a step in NO formation triggered by Ca2+-influx through NMDA receptors.