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

Samuel M. Poloyac, Yuqing Zhang, Robert R. Bies, Patrick M. Kochanek, Steven H. Graham

Research output: Contribution to journalArticle

51 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1551-1561
Number of pages11
JournalJournal of Cerebral Blood Flow and Metabolism
Volume26
Issue number12
DOIs
StatePublished - Dec 8 2006

Keywords

  • Arachidonic acid
  • Cytochrome P450
  • Hydroxyeicosatetraenoic acid
  • Middle cerebral artery occlusion
  • N-hydroxy-N-4-butyl-2-methylphenylformamidine
  • Stroke

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

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