title: Effect of a new inhibitor of the synthesis of 20-HETE on cerebral ischemia reperfusion injury.
abstract: 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.
authors.affiliation: Medicinal Research Laboratory, Taisho Pharmaceutical Co, Ltd, Saitama, Japan. t.omura@po.rd.taisho.co.jp
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Omura
authors.forename: Yu
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Miyata
authors.forename: Chie
authors.initials: C
authors.lastname: Koizumi
authors.forename: Takanobu
authors.initials: T
authors.lastname: Sakurai
authors.forename: Misako
authors.initials: M
authors.lastname: Fukasawa
authors.forename: Kenji
authors.initials: K
authors.lastname: Hachiuma
authors.forename: Toshiya
authors.initials: T
authors.lastname: Minagawa
authors.forename: Teruo
authors.initials: T
authors.lastname: Susumu
authors.forename: Shigeru
authors.initials: S
authors.lastname: Yoshida
authors.forename: Shiro
authors.initials: S
authors.lastname: Nakaike
authors.forename: Shigeru
authors.initials: S
authors.lastname: Okuyama
authors.forename: David R
authors.initials: DR
authors.lastname: Harder
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Roman
mesh_terms: 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
chemical_list: 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