Published Online
on April 6, 2006

A more recent version of this article appeared on May 1, 2006

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Submitted on February 7, 2006
Accepted on February 28, 2006

Effect of a New Inhibitor of the Synthesis of 20-HETE on Cerebral Ischemia Reperfusion Injury

Tomohiro Omura PhD^*; Yu Tanaka MS; Noriyuki Miyata PhD; Chie Koizumi MS; Takanobu Sakurai PhD; Misako Fukasawa MS; Kenji Hachiuma MS; Toshiya Minagawa PhD; Teruo Susumu MS; Shigeru Yoshida MS; Shiro Nakaike PhD; Shigeru Okuyama PhD; David R. Harder PhD; and Richard J. Roman PhD

From the Medicinal Research Laboratories (T.O., Y.T., N.M., C.K., S.Y., S.N.) and the Medicinal Development Research Laboratories (T. Sakurai, M.F., K.H., T.M., S.O.), Taisho Pharmaceutical Co, Ltd, Saitama, Japan; Shin Nippon Biomedical Laboratories Ltd (T. Susumu), Kagoshima, Japan; Cardiovascular Research Center (D.R.H.) and the Department of Physiology (R.J.R.), Medical College of Wisconsin, Milwaukee, Wisc.

^* To whom correspondence should be addressed. E-mail: t.omura{at}po.rd.taisho.co.jp.

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.

Key words: 20-HETE • brain injury • cytochrome P450 • ischemic stroke

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