Upregulation of 20-HETE Synthetic Cytochrome P450 Isoforms by Oxygen–Glucose Deprivation in Cortical Neurons

Hui Zhang, J R Falck, Richard J. Roman, David R. Harder, Raymond C. Koehler, Zeng Jin Yang

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

20-Hydroxyeicosatetraenoic acid (20-HETE), a potent vasoconstrictor, is a cytochrome P450 (CYP) 4A/4F-derived metabolite of arachidonic acid. Inhibition of 20-HETE synthesis protects brain from ischemic injury. However, that protection is not associated with changes in cerebral blood flow. The present study examined whether CYP4A isoforms are expressed in neurons, whether they produce 20-HETE in neurons, and whether neuronally derived 20-HETE exerts direct neurotoxicity after oxygen–glucose deprivation (OGD). The expression of Cyp4a10 and Cyp4a12a mRNA in cultured mouse cortical neurons increased significantly at 1 and 3 h after exposure to 1 h of OGD. Reoxygenation also markedly augmented the expression of CYP4A protein in neurons and increased 20-HETE levels in the culture medium. Cell viability after OGD increased after treatment with a 20-HETE synthesis inhibitor or an antagonist. That effect was reversed by co-administration of a 20-HETE agonist. These results indicate that neurons express Cyp4a10 and 4a12a, that expression of these isoforms is upregulated by OGD stress, and that neuronally derived 20-HETE directly contributes to neuronal death after reoxygenation.

Original languageEnglish (US)
Pages (from-to)1279-1286
Number of pages8
JournalCellular and Molecular Neurobiology
Volume37
Issue number7
DOIs
StatePublished - Oct 1 2017

Keywords

  • 20-HETE
  • Cytochrome P450
  • Eicosanoid
  • Ischemia
  • Oxygen–glucose deprivation

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Cell Biology

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