Effect of a new inhibitor of the synthesis of 20-HETE on cerebral ischemia reperfusion injury.
OBJECTIVE
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.


CONCLUSIONS
These results suggest that blockade of the formation of 20-HETE with TS-011 may be useful for the treatment of ischemic stroke.
Omura
Tomohiro
T
Medicinal Research Laboratory, Taisho Pharmaceutical Co, Ltd, Saitama, Japan. t.omura@po.rd.taisho.co.jp
Tanaka
Yu
Y
Miyata
Noriyuki
N
Koizumi
Chie
C
Sakurai
Takanobu
T
Fukasawa
Misako
M
Hachiuma
Kenji
K
Minagawa
Toshiya
T
Susumu
Teruo
T
Yoshida
Shigeru
S
Nakaike
Shiro
S
Okuyama
Shigeru
S
Harder
David R
DR
Roman
Richard J
RJ
D000818:Animals; D002545:Brain Ischemia / Q000097:blood / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D005559:Formamides / Q000494:pharmacology*; D008401:Gas Chromatography-Mass Spectrometry; D000882:Haplorhini; D006893:Hydroxyeicosatetraenoic Acids / Q000037:antagonists & inhibitors* / Q000097:blood; D008297:Male; D009025:Morpholines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000097:blood / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology
D005559:Formamides; D006893:Hydroxyeicosatetraenoic Acids; D009025:Morpholines; C503100:N-(3-chloro-4-morpholin-4-yl) phenyl-N'-hydroxyimido formamide; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid