Omura Tomohiro, Tanaka Yu, Miyata Noriyuki, Koizumi Chie, Sakurai Takanobu, Fukasawa Misako, Hachiuma Kenji, Minagawa Toshiya, Susumu Teruo, Yoshida Shigeru, Nakaike Shiro, Okuyama Shigeru, Harder David R, Roman Richard J
Medicinal Research Laboratory, Taisho Pharmaceutical Co, Ltd, Saitama, Japan.
Stroke. 2006 May;37(5):1307-13. doi: 10.1161/01.STR.0000217398.37075.07. Epub 2006 Apr 6.
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.
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.
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.
These results suggest that blockade of the formation of 20-HETE with TS-011 may be useful for the treatment of ischemic stroke.
脑缺血后释放的花生四烯酸可代谢生成20-羟基二十碳四烯酸（20-HETE）。20-HETE是一种强效血管收缩剂，可能导致缺血性损伤。本研究检测了用TS-011阻断20-HETE合成对大鼠大脑中动脉短暂闭塞（MCAO）后及猴血栓栓塞性中风后梗死灶大小的影响。
大鼠在MCAO后的不同时间用TS-011或赋形剂进行处理。通过2,3,5-氯化三苯基四氮唑（TTC）染色测量梗死灶大小，并用液相色谱-质谱联用（LC/MS）测定血浆中20-HETE的水平。在向猴颈内动脉引入血栓后，也研究了TS-011对梗死灶大小的影响。
大鼠MCAO后血浆中20-HETE水平升高。TS-011（每小时0.01至1.0毫克/千克）使梗死体积减少了40%。连续7天给予TS-011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联合使用也改善了猴中风模型的神经功能结局。
这些结果表明，用TS-011阻断20-HETE的形成可能对缺血性中风的治疗有用。
