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.
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Authors | Yu Tanaka, Tomohiro Omura, Misako Fukasawa, Nobuko Horiuchi, Noriyuki Miyata, Toshiya Minagawa, Shigeru Yoshida, Shiro Nakaike |
Journal | Neuroscience research
(Neurosci Res)
Vol. 59
Issue 4
Pg. 475-80
(Dec 2007)
ISSN: 0168-0102 [Print] Ireland |
PMID | 17933409
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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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
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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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