title: Attenuation of neonatal ischemic brain damage using a 20-HETE synthesis inhibitor.
abstract: 20-Hydroxyeicosatetraenoic acid (20-HETE) is a cytochrome P450 metabolite of arachidonic acid that that contributes to infarct size following focal cerebral ischemia. However, little is known about the role of 20-HETE in global cerebral ischemia or neonatal hypoxia-ischemia (H-I). The present study examined the effects of blockade of the synthesis of 20-HETE with N-hydroxy-N'-(4-n-butyl-2-methylphenyl) formamidine (HET0016) in neonatal piglets after H-I to determine if it protects highly vulnerable striatal neurons. Administration of HET0016 after H-I improved early neurological recovery and protected neurons in putamen after 4 days of recovery. HET0016 had no significant effect on cerebral blood flow. cytochrome P450 4A immunoreactivity was detected in putamen neurons, and direct infusion of 20-HETE in the putamen increased phosphorylation of Na(+), K(+) -ATPase and NMDA receptor NR1 subunit selectively at protein kinase C-sensitive sites but not at protein kinase A-sensitive sites. HET0016 selectively inhibited the H-I induced phosphorylation at these same sites at 3 h of recovery and improved Na(+), K(+) -ATPase activity. At 3 h, HET0016 also suppressed H-I induced extracellular signal-regulated kinase 1/2 activation and protein markers of nitrosative and oxidative stress. Thus, 20-HETE can exert direct effects on key proteins involved in neuronal excitotoxicity in vivo and contributes to neurodegeneration after global cerebral ischemia in immature brain.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD 21205, USA. zyang4@jhmi.edu
authors.forename: Zeng-Jin
authors.initials: ZJ
authors.lastname: Yang
authors.forename: Erin L
authors.initials: EL
authors.lastname: Carter
authors.forename: Kathleen K
authors.initials: KK
authors.lastname: Kibler
authors.forename: Herman
authors.initials: H
authors.lastname: Kwansa
authors.forename: Daina A
authors.initials: DA
authors.lastname: Crafa
authors.forename: Lee J
authors.initials: LJ
authors.lastname: Martin
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Roman
authors.forename: David R
authors.initials: DR
authors.lastname: Harder
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Koehler
mesh_terms: D000578:Amidines / Q000008:administration & dosage*; D000818:Animals; D000831:Animals, Newborn; D002545:Brain Ischemia / Q000378:metabolism* / Q000517:prevention & control*; D006893:Hydroxyeicosatetraenoic Acids / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D057967:Infusions, Intraventricular; D008297:Male; D013552:Swine
chemical_list: D000578:Amidines; C000708209:HET0016; D006893:Hydroxyeicosatetraenoic Acids; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid