Overexpression of heme oxygenase-1 is neuroprotective in a model of permanent middle cerebral artery occlusion in transgenic mice

Heme oxygenase-l (HO-1, HSP32) is an early gene that is responsive to an ar ray of pathological conditions including, but not limited to, hypoxia and c erebral ischemia. HO-I cleaves the heme molecule and produces carbon monoxi de (CO) and biliverdin (an antioxidant) and is essential for iron homeostas is, The purpose of this study was to investigate, using transgenic (Tg) mic e, whether overexpression of HO-1 in the brain augments or attenuates cellu lar injury caused by ischemic stroke. Homozygous HO-1 Tg mice that overexpr ess HO-1 under the control of the neuron-specific enolase promoter (charact erized previously) were used. Under halothane anesthesia and normothermic c onditions, wildtype nontransgenic (nTg; n = 22) and HO-1 Tg (n = 24) mice w ere subjected to middle cerebral artery occlusion (MCAo). Six hours after i nduction of ischemia, Tg and nTg mice developed infarcts that were 39 +/- 6 and 63 +/- 9 mm(3), respectively (p < 0.01), No significant difference bet ween the two strains was observed in the values of brain edema (11.3 +/- 4% in Tg vs. 14.6 +/- 5% in nTg; p < 0.1), At 24 h after MCAo, Tg mice exhibi ted significant neuroprotection as determined by the stroke volumes (41 +/- -2 mm(3) in Tg vs. 74 +/- 5 mm(3) in nTg; p < 0.01) and values of ischemic cerebral edema (21 +/- 6% in Tg vs. 35 +/- 11% in nTg; p < 0.01), Data sug gest that neuroprotection in Tg mice was, at least in part, related to the following findings: (a) constitutively up-regulated cyclic GMP and bcl-2 le vels in neurons; (b) inhibition of nuclear localization of p53 protein; and (c) antioxidant action of HO-l,as detected by postischemic neuronal expres sion of ferritin, and decreases in iron staining and tissue lipid peroxidat ion. We suggest that pharmacological stimulation of HO-1 activity may const itute a novel therapeutic approach in the amelioration of ischemic injury d uring the acute period of stroke.