Heme oxygenase-2 is neuroprotective in cerebral ischemia

Heme oxygenase (HO) is believed to be a potent antioxidant enzyme in the ne rvous system; it degrades her-ne from heme-containing proteins, giving rise to carbon monoxide, iron, and biliverdin, which is rapidly reduced to bili rubin. The first identified isoform of the enzyme, HO1, is an inducible hea l-shock protein expressed in high levels in peripheral organs and barely de tectable under normal conditions in the brain, whereas HO2 is constitutive and most highly concentrated in the brain. interestingly, although HO2 is c onstitutively expressed, its activity can be modulated by phosphorylation. We demonstrated that bilirubin, formed from HO2, is neuroprotectant, as neu rotoxicity is augmented in neuronal cultures from mice with targeted deleti on of HO2 (HO2(-/-)) and reversed by low concentrations of bilirubin. We no w show that neural damage following middle cerebral artery occlusion (MCAO) and reperfusion, a model of focal ischemia of vascular stroke, is substant ially worsened in HO2(-/-) animals. By contrast, stroke damage is nor signi ficantly altered in HO1(-/-) mice, despite their greater debility. Neural d amage following intracranial injections of N-methyl-D-aspartate (NMDA) is a lso accentuated in HO2(-/-) animals. These findings establish HO2 as an end ogenous neuroprotective system in the brain whose pharmacologic manipulatio n may have therapeutic relevance.