Heme oxygenase-2 is neuroprotective in cerebral ischemia

S. Doré, K. Sampei, S. Goto, N. J. Alkayed, D. Guastella, S. Blackshaw, M. Gallagher, R. J. Traystman, P. D. Hurn, R. C. Koehler, S. H. Snyder

Research output: Contribution to journalArticle

133 Scopus citations

Abstract

Heme oxygenase (HO) is believed to be a potent antioxidant enzyme in the nervous system; it degrades heme from heme-containing proteins, giving rise to carbon monoxide, iron, and biliverdin, which is rapidly reduced to bilirubin. The first identified isoform of the enzyme, HO1, is an inducible heat-shock protein expressed in high levels in peripheral organs and barely detectable under normal conditions in the brain, whereas HO2 is constitutive and most highly concentrated in the brain. Interestingly, although HO2 is constitutively expressed, its activity can be modulated by phosphorylation. We demonstrated that bilirubin, formed from HO2, is neuroprotectant, as neurotoxicity is augmented in neuronal cultures from mice with targeted deletion of HO2 (HO2-/-) and reversed by low concentrations of bilirubin. We now show that neural damage following middle cerebral artery occlusion (MCAO) and reperfusion, a model of focal ischemia of vascular stroke, is substantially worsened in HO2-/- animals. By contrast, stroke damage is not significantly altered in HO1-/- mice, despite their greater debility. Neural damage following intracranial injections of N-methyl-D-aspartate (NMDA) is also accentuated in HO2-/- animals. These findings establish HO2 as an endogenous neuroprotective system in the brain whose pharmacologic manipulation may have therapeutic relevance.

Original languageEnglish (US)
Pages (from-to)656-663
Number of pages8
JournalMolecular Medicine
Volume5
Issue number10
DOIs
StatePublished - 1999

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Doré, S., Sampei, K., Goto, S., Alkayed, N. J., Guastella, D., Blackshaw, S., Gallagher, M., Traystman, R. J., Hurn, P. D., Koehler, R. C., & Snyder, S. H. (1999). Heme oxygenase-2 is neuroprotective in cerebral ischemia. Molecular Medicine, 5(10), 656-663. https://doi.org/10.1007/bf03401984