Post-treatment of transient focal cerebral ischemia in rats with the novel cerebrovascular-selective Ca2+ channel antagonist (+/-)-(E)-1-(3-fluoro-6,11-dihydrodibenz[b,e]-oxepine-11-yl)-4-(3-pheny l-2-propenyl)-piperazine dimaleate.
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.
Minato
H
H
Department of Pharmacology I, Dainippon Pharmaceutical Co., Ltd., Osaka Japan.
Kikuta
C
C
Masuda
Y
Y
Fujitani
B
B
Hosoki
K
K
D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000473:pathology*; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D002540:Cerebral Cortex / Q000473:pathology; D002544:Cerebral Infarction / Q000473:pathology / Q000517:prevention & control; D003990:Dibenzoxepins / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D002546:Ischemic Attack, Transient / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D008689:Methacrylates / Q000627:therapeutic use; D010879:Piperazines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors
D002121:Calcium Channel Blockers; D003990:Dibenzoxepins; D004791:Enzyme Inhibitors; D008689:Methacrylates; D010879:Piperazines; C077479:AJ 3941; D013930:Thromboxane-A Synthase; C034364:ozagrel