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J Neurochem. 2012 Apr;121(1):168-79. doi: 10.1111/j.1471-4159.2012.07666.x. Epub 2012 Feb 2.

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

Author information

  • 1Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD 21205, USA. zyang4@jhmi.edu

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.

© 2012 The Authors. Journal of Neurochemistry © 2012 International Society for Neurochemistry.

PMID:
22251169
[PubMed - indexed for MEDLINE]
PMCID:
PMC3303996
Free PMC Article

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