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

Abstract

AbstractThe expression of hypoxia‐inducible factor‐1‐alpha (HIF‐1α) is upregulated in ischemic stroke, but its function is still unclear. In the present study, biphasic expression of HIF‐1α 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‐1α 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‐1α 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‐1α 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‐1α expression in neurons after ischemic stroke.