Attenuation of neonatal ischemic brain damage using a 20-HETE synthesis inhibitor

Zeng Jin Yang, Erin L. Carter, Kathleen K. Kibler, Herman Kwansa, Daina A. Crafa, Lee J Martin, Richard J. Roman, David R. Harder, Raymond C Koehler

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)168-179
Number of pages12
JournalJournal of Neurochemistry
Volume121
Issue number1
DOIs
StatePublished - Apr 2012

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Keywords

  • cerebral blood flow
  • cytochrome P450 4A
  • HET0016
  • K -ATPase
  • Na
  • NMDA receptor
  • piglet

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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