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Continuous inhibition of 20-HETE synthesis by TS-011 improves neurological and functional outcomes after transient focal cerebral ischemia in rats.

Abstract
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.
AuthorsYu Tanaka, Tomohiro Omura, Misako Fukasawa, Nobuko Horiuchi, Noriyuki Miyata, Toshiya Minagawa, Shigeru Yoshida, Shiro Nakaike
JournalNeuroscience research (Neurosci Res) Vol. 59 Issue 4 Pg. 475-80 (Dec 2007) ISSN: 0168-0102 [Print] Ireland
PMID17933409 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Formamides
  • Hydroxyeicosatetraenoic Acids
  • Morpholines
  • N-(3-chloro-4-morpholin-4-yl) phenyl-N'-hydroxyimido formamide
  • Neuroprotective Agents
  • 20-hydroxy-5,8,11,14-eicosatetraenoic acid
Topics
  • Animals
  • Brain (drug effects, metabolism, physiopathology)
  • Brain Ischemia (drug therapy, metabolism, physiopathology)
  • Cerebral Arteries (drug effects, metabolism)
  • Cerebrovascular Circulation (drug effects, physiology)
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Formamides (pharmacokinetics, therapeutic use)
  • Hydroxyeicosatetraenoic Acids (antagonists & inhibitors, biosynthesis)
  • Ischemic Attack, Transient (drug therapy, metabolism, physiopathology)
  • Morpholines (pharmacokinetics, therapeutic use)
  • Neuroprotective Agents (pharmacology, therapeutic use)
  • Rats
  • Rats, Sprague-Dawley
  • Treatment Outcome
  • Up-Regulation (drug effects, physiology)
  • Vasodilation (drug effects, physiology)

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