Watanabe T, Yuki S, Egawa M, Nishi H
Pharmaceuticals Laboratory I, Mitsubishi Kasei Corporation, Yokohama, Japan.
J Pharmacol Exp Ther. 1994 Mar;268(3):1597-604.
The anti-ischemic effects and a possible mechanism of a new antistroke agent, 3-methyl-1-phenyl-pyrazolin-5-one (MCI-186), were studied. Preischemic treatment with MCI-186 (3 mg/kg i.v.) facilitated the recovery of electrocorticographic activity and prolonged survival time in global complete ischemia of rats; MCI-186 (1 and 3 mg/kg i.v.) also mitigated dysfunction of the blood-brain barrier and energy failure in hemispheric embolization of rats. Postischemic treatment with MCI-186 (3 mg/kg i.v.) decreased cortical infarction in focal embolization of rats. MCI-186 (0.6-2.4 mM) inhibited the OH.-induced hydroxylation of salicylate (maximal inhibition, 40.2%), but at 100 microM it did not influence O2- generation. MCI-186 inhibited the formation of linoleic acid-conjugated dienes caused by OH. (IC50 = 32.0 microM). Also, concurrent administration of MCI-186 (3-100 mg/kg i.v.) ameliorated hyperglycemia, hyperlipopeoxidemia and degranulation of beta-cells in alloxan (40 mg/kg i.v.)-treated rats. In addition, MCI-186 inhibited iron-dependent peroxidation in rat brain homogenates and mitochondrial homogenates (IC50 = 15.0 and 2.3 microM, respectively) and prevented iron-dependent peroxidative disintegration of mitochondrial membranes (IC50 = 39.0 microM). These findings suggest that MCI-186 has potent anti-ischemic actions and that its mechanism may be closely associated with beneficial antioxidant activities.
研究了新型抗中风药物3-甲基-1-苯基-吡唑啉-5-酮（MCI-186）的抗缺血作用及其可能机制。MCI-186（3mg/kg静脉注射）缺血预处理可促进大鼠全脑完全缺血时皮层脑电图活动的恢复并延长存活时间；MCI-186（1和3mg/kg静脉注射）还可减轻大鼠半球栓塞时血脑屏障功能障碍和能量衰竭。MCI-186（3mg/kg静脉注射）缺血后处理可减少大鼠局灶性栓塞时的皮层梗死。MCI-186（0.6 - 2.4mM）可抑制OH·诱导的水杨酸羟基化（最大抑制率为40.2%），但在100μM时不影响O2-的生成。MCI-186可抑制OH·引起的亚油酸共轭二烯的形成（IC50 = 32.0μM）。此外，同时给予MCI-186（3 - 100mg/kg静脉注射）可改善四氧嘧啶（40mg/kg静脉注射）处理大鼠的高血糖、高脂过氧化血症和β细胞脱颗粒。另外，MCI-186可抑制大鼠脑匀浆和线粒体匀浆中铁依赖性过氧化反应（IC50分别为15.0和2.3μM），并防止线粒体膜铁依赖性过氧化解体（IC50 = 39.0μM）。这些结果表明，MCI-186具有强大的抗缺血作用，其机制可能与有益的抗氧化活性密切相关。
