Protective effects of U-92032, a novel Ca2+ blocker with anti-peroxidative activity, on cerebral ischemic injury

U-92032, (7-「「4-「bis(4-Fluorophenyl)methyl」-1-piperazinyl」 methyl」-2-「(2-hydroxyethyl)amino」4-(1-methylethyl)-2,4,6-cycloheptatrien-1-one) is a novel calcium channel blocker with anti-peroxidative activity. We investigated the anti-ischemic and anoxic effects of U-92032 in a number of models in rodents. In in vitro hypoxia injury, U-92032 at 3x10^-6 M had protective action against functional failure of CA1 neuron in hippocampal slice after 10 min hypoxia/hypoglycemia. In KCN anoxia, U-92032 at a dose of 10 mg/kg, i.v. or 100 mg/kg, p.o. prevented lethality in mice. In stroke model in gerbils, U-92032 at 10 mg/kg, p.o, reduced stroke index induced by unilateral ligation of the carotid artery. Following transient global ischemia, U-92032 had protective action against delayed neuronal death in hippocampus and improved impairment of passive avoidance performance. U-92032 also had a selective vasodilating action of cerebral artery (IC_50 =3.2x10^-7 M) in vitro and increased cerebral blood flow in vivo. These results demonstrate cerebroprotective efficaey of U-92032 in a number of cerebral ischemia models.