HIF-1 alpha inhibition ameliorates neonatal brain damage after hypoxic-ischemic injury

Abstract

Background Hypoxia-inducible-factor-1alpha (HIF-1α) has been considered as a regulator of both prosurvival and prodeath pathways in the nervous system. This study was designed to elucidate the role of HIF-1α in neonatal hypoxia-ischemia (HI) brain injury. Methods 2-methoxyestradiol (2ME2), a HIF-1α inhibitor, was tested at different dosages (1.5, 15 and 150 mg/kg) and a therapeutic window was tested by administrating 2-methoxyestradiol (15 mg/kg) immediately or 3 hours after the induction of a hypoxic ischemic injury. Infarct size using TTC staining and brain edema were measured at 48 hours post hypoxia-ischemia. Blood-brain barrier (BBB) permeability was examined by IgG staining. Vascular endothelial growth factor (VEGF) and HIF-1α expression and distribution were studied by immunohistochemistry and western blotting analysis. Findings 2ME2 exhibited dose-dependent neuroprotection by decreasing infarct volume and attenuating brain edema. 2ME2 also attenuated BBB disruption, and decreased HIF-1α and vascular endothelial growth factor (VEGF) expression. The neuroprotection, however, was lost when 2ME2 was administered 3 hours after neonatal HI. Conclusion The study shows that the acute inhibition of HIF-1α is neuroprotective in neonatal hypoxic-ischemic injury by preserving BBB integrity and reducing brain edema. © 2008 Springer-Verlag/Wien.