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

Fingerprint

Brain
Ischemia
Putamen
Brain Ischemia
Neurons
Phosphorylation
Recovery
Cytochrome P-450 Enzyme System
Adenosine Triphosphatases
Cerebrovascular Circulation
Corpus Striatum
Oxidative stress
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Metabolites
Cyclic AMP-Dependent Protein Kinases
Arachidonic Acid
Protein Kinase C
Proteins
Oxidative Stress

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Attenuation of neonatal ischemic brain damage using a 20-HETE synthesis inhibitor. / Yang, Zeng Jin; Carter, Erin L.; Kibler, Kathleen K.; Kwansa, Herman; Crafa, Daina A.; Martin, Lee J; Roman, Richard J.; Harder, David R.; Koehler, Raymond C.

In: Journal of Neurochemistry, Vol. 121, No. 1, 04.2012, p. 168-179.

Research output: Contribution to journalArticle

Yang, Zeng Jin ; Carter, Erin L. ; Kibler, Kathleen K. ; Kwansa, Herman ; Crafa, Daina A. ; Martin, Lee J ; Roman, Richard J. ; Harder, David R. ; Koehler, Raymond C. / Attenuation of neonatal ischemic brain damage using a 20-HETE synthesis inhibitor. In: Journal of Neurochemistry. 2012 ; Vol. 121, No. 1. pp. 168-179.
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