POSTTREATMENT OF TRANSIENT FOCAL CEREBRAL-ISCHEMIA IN RATS WITH THE NOVEL CEREBROVASCULAR-SELECTIVE CA2+ CHANNEL ANTAGONIST (+ ]-OXEPINE-11-YL)4-(3-PHENYL-2-PROPENYL)-PIPERAZINE DIMALEATE/

The efficacy of post-ischemic treatment with AJ-3941 -oxepine-11-yl)-4 -(3-phenyl-2-propenyl)-piperazine dimaleate, CAS 143110-70-7), a cereb rovascular selective Ca2+ channel antagonist, on brain infarction indu ced by focal ischemia-reperfusion in rats was evaluated. Focal ischemi a was induced by transient occlusion of middle cerebral artery (MCA) w ith a 3-0 nylon monofilament for 90 min. One day after MCA occlusion ( MCAo), brain infarct size was determined by measuring 2,3,5-triphenylt etrazonium chloride-negative stained area of the serial brain sections . The development of cerebral infarction was observed in both regions of cortex and subcortex, such as striatum, caudatum, putamen, hippocam pus and corpus callosum. Post-ischemic treatment with AJ-3941 (1 or 3 mg/kg p.o., 10 min and 3 h after the occlusion) significantly reduced the infarct size and volume in the ipsilateral hemisphere in a dose-de pendent manner, compared to the solvent control. The reducing effect w as observed mainly in the cortical region, and a significant reduction of the subcortical infarct volume was found at the higher dose (3 mg/ kg). Post-ischemic treatment with the thromboxane A(2) synthetase inhi bitor, sodium ozagrel (150 mu g/kg/min i.v. infusion, between 1 h and 24 h after the MCAo) did not reduce the infarct volume in the hemisphe re after ischemia-reperfusion. AJ-3941 had only minimum effect on the elevation of body temperature during ischemia-reperfusion. These resul ts indicate that post-ischemic treatment with AJ-3941 may ameliorate t he brain injury after the transient focal cerebral ischemia, and they suggest that AJ-3941 has beneficial effects for treatment of ischemic cerebral damage, such as stroke.