21-aminosteroid lipid peroxidation inhibitor u74006f protects against cerebral ischemia in gerbils

U74006F(21-[4-(2,6-di-l-pyrrolidiny1-4-pyrimidinyl)-1-piperazinyl]-16a-met triene-3,20-dione, monomethane sulfonate) is a novel and potent inhibitor of central nervous system tissue lipid peroxidation that is devoid of classical steroid hormonal activities. Its possible efficacy in attenuating postischemic mortality and neuronai necrosis was examined in gerbils following 3-hour unilateral carotid artery occlusion. Male Mongolian gerbils received two intraperitoneal injections of either vehicle or U74006F (3 or 10 mg/kg), the first injection 10 minutes before and the second injection at the end of the 3-hour ischemic episode. In an initial series of experiments, vehicle-treated gerbils displayed 60.9% (14 of 23) survival 24 hours after ischemia, which decreased to 34.8% (8 of 23) at 48 hours. In contrast, the 10 mg/kg U74006F-treated group showed 86.7% (13 of 15) survival at 24 hours (p<0.15 vs. vehicle) and 80.0% (12 of 15) survival at 48 hours (p<0.02). In a second series, neurons in the hippocampal CA, subfield and the medial and lateral cerebral cortex were counted in gerbils surviving 24 hours after unilateral carotid artery occlusion. Comparison of neuronai densities in the ischemic hemisphere with those in the contralateral nonischemic hemisphere revealed significant neuronai preservation in all three brain regions of 10 mg/kg i.p. × 2 U74006F-treated gerbils. Our results show that U74006F can improve survival and attenuate neuronai necrosis in a severe brain ischemia model. Because U74006F is a potent inhibitor of lipid peroxidation, its anti-ischemic efficacy supports an important role of oxygen radical-induced lipid peroxidation in the pathophysiology of brain ischemia with reperfusion; however, other therapeutic mechanisms may also be involved.