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 journalArticlepeer-review

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

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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