Protective effect of the 20-HETE inhibitor HET0016 on brain damage after temporary focal ischemia.

Cytochrome P450 metabolism of arachidonic acid produces the potent vasoconstrictive metabolite, 20-hydroxyeicosatetraenoic acid (20-HETE). Recent studies have implicated 20-HETE as a vasoconstrictive mediator in hemorrhagic stroke. The purpose of this study was to determine the effect of the 20-HETE inhibitor, HET0016, on lesion volume and cerebral blood flow (CBF) after temporary middle cerebral artery occlusion (MCAO) in rats. Plasma pharmacokinetics and tissue concentrations of HET0016 were determined after a 10 mg/kg intraperitoneal dose. Separate rats were treated with HET0016 or vehicle before 90 mins of MCAO. Lesion volume was assessed by 2,3,5-triphenyl-tetrazolium-chloride and cerebral flow was determined using laser Doppler flow. The effect of MCAO on in vitro microsomal formation of mono-oxygenated arachidonic acid metabolites was also determined. Results show that HET0016 has a short biologic half-life, distributes into the brain, and is associated with a 79.6% reduction in 20-HETE concentration in the cortex. Lesion volume was greatly reduced in HET0016-treated (9.1%+/-4.9%) versus vehicle-treated (57.4%+/-9.8%; n=6; P<0.001) rats. An attenuation of the observed decrease in CBF was observed in HET0016-treated (180 mins 89.2%+/-6.2%; 240 mins 88.1%+/-5.7% of baseline flow) versus vehicle control (180 mins 57.6%+/-19.0%; 240 mins 53.8%+/-20.0% of baseline flow; n=6; P<0.05). Brain cortical microsomal formation rate of 20-HETE was also reduced at 24 h in the ipsilateral hemisphere after MCAO. These data support a significant role for 20-HETE in the pathogenesis of ischemic stroke.
AuthorsSamuel M Poloyac, Yuqing Zhang, Robert R Bies, Patrick M Kochanek, Steven H Graham
JournalJournal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (J Cereb Blood Flow Metab) Vol. 26 Issue 12 Pg. 1551-61 (Dec 2006) ISSN: 0271-678X [Print] United States
PMID16570075 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Amidines
  • Hydroxyeicosatetraenoic Acids
  • N-hydroxy-N'-(4-butyl-2-methylphenyl)formamidine
  • 20-hydroxy-5,8,11,14-eicosatetraenoic acid
  • Cytochrome P-450 Enzyme System
  • Amidines (pharmacokinetics, pharmacology)
  • Animals
  • Brain Injuries (metabolism, pathology)
  • Brain Ischemia (metabolism, pathology)
  • Cerebrovascular Circulation (drug effects)
  • Cytochrome P-450 Enzyme System (metabolism)
  • Hydroxyeicosatetraenoic Acids (antagonists & inhibitors, metabolism)
  • Male
  • Microsomes (metabolism, pathology)
  • Rats
  • Rats, Sprague-Dawley
  • Reperfusion Injury (metabolism, pathology)
  • Stroke (metabolism, pathology)
  • Vasoconstriction (drug effects)

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