Selective Inhibition of Early-but Not Late-Expressed HIF-1α Is Neuroprotective in Rats after Focal Ischemic Brain Damage

The expression of hypoxia-inducible factor-1-alpha (HIF-1 alpha) is upregulated in ischemic stroke, but its function is still unclear. In the present study, biphasic expression of HIF-1 alpha was observed during 1-12 h and after 48 h in neurons exposed to ischemic stress in vitro and in vivo. Treating neurons with 2-methoxyestradiol (2ME2) 0.5 h after ischemic stress or pre-silencing HIF-1 alpha with small interfering RNA (siRNA) decreased brain injury, brain edema and number of apoptotic cell, and downregulates Nip-like protein X (Nix) expression. Conversely, applying 2ME2 to neurons 8 h after ischemic stress or silencing the HIF-1 alpha with siRNA 12 h after oxygen-glucose deprivation (OGD) increased neuron damage and decreased vascular endothelial growth factor (VEGF) expression. Taken together, these results demonstrate that HIF-1 alpha induced by ischemia in early and late times leads cellular apoptosis and survival, respectively, and provides a new insight into the divergent roles of HIF-1 alpha expression in neurons after ischemic stroke.