Effect of a new inhibitor of the synthesis of 20-HETE on cerebral ischemia reperfusion injury
Effect of a new inhibitor of the synthesis of 20-HETE on cerebral ischemia reperfusion injury
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DOI：
10.1161/01.str.0000217398.37075.07
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发表时间：
2006-05-01
期刊：
影响因子：
8.3
通讯作者：
Roman, RJ
中科院分区：
文献类型：
--
作者：
Omura, T;Tanaka, Y;Roman, RJ
背景和目的-脑缺血后释放的花生四烯酸可代谢为20-羟基二十碳四烯酸（20-HETE）。20-HETE是一种可能导致缺血性损伤的强效血管收缩剂。本研究探讨了阻断合成的20-HETE与TS-011对梗死面积短暂闭塞后大脑中动脉（MCAO）的大鼠和thromboembolic stroke in monkeys. Methods后，大鼠进行了治疗与TS-011或车辆在不同的时间后MCAO。通过2，3，5-氯化三苯基四氮唑（TTC）染色测量血小板大小，并通过液相色谱/质谱（LC/MS）测定血浆20-HETE水平。TS-011对梗塞面积的影响也进行了研究，在猴子引入一个凝块到颈内动脉。结果，血浆水平的20-HETE增加后，MCAO大鼠。TS-011（0.01至1.0 mg/ kg/h）使梗死体积减少40%。TS-011长期给药7天可减轻大鼠MCAO后的神经功能缺损。TS-011与组织型纤溶酶原激活剂的组合也改善了神经功能的结果在中风模型中monkeys. Conclusion-这些结果表明，封锁的形成20- HETE与TS-011可能是有用的缺血性中风的治疗。
Background and Purpose-Arachidonic acid that is released following cerebral ischemia can be metabolized to 20-hydroxyeicosatetraenoic acid (20-HETE). 20-HETE is a potent vasoconstrictor that may contribute to ischemic injury. This study examined the effects of blockading the synthesis of 20-HETE with TS-011 on infarct size after transient occlusion of the middle cerebral artery (MCAO) of rats and after thromboembolic stroke in monkeys.Methods-Rats were treated with TS-011 or vehicle at various times after MCAO. Infarct size was measured by 2,3,5-triphenyltetrazolium chloride (TTC) staining and plasma levels of 20-HETE were determined by liquid chromatography mass spectrometry (LC/MS). The effect of TS-011 on infarct size was also studied in monkeys after introduction of a clot into the internal carotid artery.Results-Plasma levels of 20-HETE increased after MCAO in rats. TS-011 (0.01 to 1.0 mg/ kg per hour) reduced infarct volume by 40%. Chronic administration of TS-011 for 7 days reduced neurological deficits after MCAO in rats. TS-011 given in combination with tissue plasminogen activator also improved neurological outcome in the stroke model in monkeys.Conclusion-These results suggest that blockade of the formation of 20- HETE with TS-011 may be useful for the treatment of ischemic stroke.