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

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 siz...

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Bibliographic Details
Published in:Stroke (1970) 2006-05, Vol.37 (5), p.1307-1313
Main Authors: OMURA, Tomohiro, TANAKA, Yu, NAKAIKE, Shiro, OKUYAMA, Shigeru, HARDER, Phi David R, ROMAN, Richard J, MIYATA, Noriyuki, KOIZUMI, Chie, SAKURAI, Takanobu, FUKASAWA, Misako, HACHIUMA, Kenji, MINAGAWA, Toshiya, SUSUMU, Teruo, YOSHIDA, Shigeru
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Brain Ischemia - blood
Brain Ischemia - drug therapy
Brain Ischemia - pathology
Brain Ischemia - physiopathology
Dose-Response Relationship, Drug
Formamides - pharmacology
Gas Chromatography-Mass Spectrometry
Haplorhini
Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy
Hydroxyeicosatetraenoic Acids - antagonists & inhibitors
Hydroxyeicosatetraenoic Acids - blood
Male
Medical sciences
Morpholines - pharmacology
Nervous system (semeiology, syndromes)
Neurology
Neuropharmacology
Neuroprotective agent
Pharmacology. Drug treatments
Rats
Rats, Wistar
Reperfusion Injury - blood
Reperfusion Injury - drug therapy
Reperfusion Injury - pathology
Reperfusion Injury - physiopathology
Vascular diseases and vascular malformations of the nervous system
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Summary: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. 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. 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. These results suggest that blockade of the formation of 20-HETE with TS-011 may be useful for the treatment of ischemic stroke.
ISSN:0039-2499
1524-4628
DOI:10.1161/01.str.0000217398.37075.07