aj-3941 and Cerebral-Infarction

The efficacy of post-ischemic treatment with AJ-3941 ((+/-)-(E)-1-(3-fluoro-6,11-dihydrodibenz[b,e]-oxepine-11-yl )-4-(3-phenyl-2- propenyl)-piperazine dimaleate, CAS 143110-70-7), a cerebrovascular selective Ca2+ channel antagonist, on brain infarction induced by focal ischemia-reperfusion in rats was evaluated. Focal ischemia was induced by transient occlusion of middle cerebral artery (MCA) with a 3-0 nylon monofilament for 90 min. One day after MCA occlusion (MCAo), brain infarct size was determined by measuring 2,3,5-triphenyltetrazonium 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, hippocampus 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-dependent manner, compared to the solvent control. The reducing effect was 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 A2 synthetase inhibitor, sodium ozagrel (150 micrograms/kg/min i.v. infusion, between 1 h and 24 h after the MCAo) did not reduce the infarct volume in the hemisphere after ischemia-reperfusion. AJ-3941 had only minimum effect on the elevation of body temperature during ischemia-reperfusion. These results indicate that post-ischemic treatment with AJ-3941 may ameliorate the 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.

Topics: Animals; Body Temperature; Brain; Calcium Channel Blockers; Cerebral Cortex; Cerebral Infarction; Dibenzoxepins; Enzyme Inhibitors; Ischemic Attack, Transient; Male; Methacrylates; Piperazines; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Thromboxane-A Synthase

In this study the effect of post-ischemic treatment of AJ-3941 ((+/-)-(E)-1-(3-fluoro-6,11-dihydrodibenz [b,e]-oxepine-11-yl)-4-(3-phenyl-2-propenyl)-piperazine dimaleate, CAS 143110-70-7) a cerebrovascular-selective calcium antagonist, on brain infarction and edema in a rat model of focal cerebral ischemia with permanent middle cerebral artery occlusion (MCAo) was evaluated. Brain infarct size was determined at 24 h after MCAo by measuring 2,3,5-triphenyltetrazolium chloride-negative stained area of the serial brain sections. Post-ischemic treatment of AJ-3941 (3 mg/kg p.o.), 10 min and 3 h after the insult, significantly reduced brain infarct size by 44-80%, compared to vehicle control. The reducing effect was observed both in the cortical and subcortical regions. Three days after MCAo, contents of water and Na+ in the ipsilateral hemisphere significantly increased comparing with those in control rats. Post-ischemic treatment with AJ-3941 (3 and 10 mg/kg twice daily p.o. for 2 days) markedly inhibited the increase in water content and suppressed the increase in Na+ content. In the contralateral hemisphere, these contents showed no significant differences between vehicle-treated group and either control (non-operated) or AJ-3941-treated group. AJ-3941 had only minimum effect on body temperature and physiological parameters, such as blood pressure, blood gases and glucose, even when the maximum dose used (10 mg/kg) was repeatedly administered. These results indicate that post-ischemic treatment with AJ-3941 may ameliorate the brain infarction and edema after permanent focal cerebral ischemia, and they also suggest that AJ-3941 has a beneficial effect in the treatment of ischemic cerebral damage.

Topics: Animals; Blood Gas Analysis; Blood Glucose; Blood Pressure; Body Temperature; Body Water; Brain Edema; Brain Ischemia; Calcium Channel Blockers; Cerebral Arteries; Cerebral Infarction; Dibenzoxepins; Male; Piperazines; Rats; Rats, Sprague-Dawley; Sodium