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.
Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA. poloyac@pitt.edu
Samuel M
SM
Poloyac
Yuqing
Y
Zhang
Robert R
RR
Bies
Patrick M
PM
Kochanek
Steven H
SH
Graham
D000578:Amidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001930:Brain Injuries / Q000378:metabolism* / Q000473:pathology; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology; D002560:Cerebrovascular Circulation / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006893:Hydroxyeicosatetraenoic Acids / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D008861:Microsomes / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology; D020521:Stroke / Q000378:metabolism / Q000473:pathology; D014661:Vasoconstriction / Q000187:drug effects
D000578:Amidines; C000708209:HET0016; D006893:Hydroxyeicosatetraenoic Acids; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D003577:Cytochrome P-450 Enzyme System