Continuous inhibition of 20-HETE synthesis by TS-011 improves neurological and functional outcomes after transient focal cerebral ischemia in rats.
TS-011, a potent and selective inhibitor of 20-HETE synthesis, has been described as providing significant benefits in animal stroke models. However, no studies have investigated changes in brain 20-HETE levels after cerebral ischemia. Also lacking are studies of TS-011 pharmacodynamics with respect to brain 20-HETE levels that may explain the benefits of TS-011 in animal models of ischemic stroke. The present study sought to explore changes in 20-HETE levels in brain tissue, as well as in plasma, after a 90-min episode of transient focal cerebral ischemia. Pharmacodynamics of TS-011 were also examined. Then, we evaluated the long-term effects of TS-011 when administered as in this pharmacodynamics study. The major findings of the present study are as follows: (1) brain 20-HETE levels increased significantly within 7.5h after MCAO; (2) TS-011 at doses of 0.1 and 0.3mg/kg administered at regular 6-h intervals appeared to reduce brain 20-HETE levels continuously; (3) TS-011 when administered as in this pharmacodynamics study improved long-term neurological and functional outcomes. These findings strongly suggest that 20-HETE plays an important role in the development of neurological and functional deficits after focal cerebral ischemia and that TS-011 may provide benefits in patients suffering ischemic stroke.
Tanaka
Yu
Y
Molecular Function and Pharmacology Laboratories, Taisho Pharmaceutical Co Ltd, Saitama, Japan. yu.tanaka@po.rd.taisho.co.jp
Omura
Tomohiro
T
Fukasawa
Misako
M
Horiuchi
Nobuko
N
Miyata
Noriyuki
N
Minagawa
Toshiya
T
Yoshida
Shigeru
S
Nakaike
Shiro
S
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism* / Q000503:physiopathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D002536:Cerebral Arteries / Q000187:drug effects / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005559:Formamides / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006893:Hydroxyeicosatetraenoic Acids / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D002546:Ischemic Attack, Transient / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D009025:Morpholines / Q000493:pharmacokinetics* / Q000627:therapeutic use; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D016896:Treatment Outcome; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
D005559:Formamides; D006893:Hydroxyeicosatetraenoic Acids; D009025:Morpholines; C503100:N-(3-chloro-4-morpholin-4-yl) phenyl-N'-hydroxyimido formamide; D018696:Neuroprotective Agents; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid