Early inhibition of HIF-1α with small interfering RNA reduces ischemic-reperfused brain injury in rats

Hypoxia-inducible factor-1 (HIF-1) plays an essential role in cerebral ischemia as a proapoptotic factor. We hypothesized that HIF-1 alpha siRNA can protect the brain from ischemic damage by inhibiting HIF-1 alpha induced apoptotic pathway at the RNA level in a rat focal ischemic model. Results showed that treatment with HIF-1 alpha siRNA reduced the infarct volume, decreased mortality, improved neurological deficits and reduced Evans blue extravasation. The expression of HIF-1 alpha mRNA (Real-Time PCR) and protein were significantly silenced and the immunohistochemistry and Western blot revealed the suppression of HIF-1 alpha, VEGF, p53 and Caspase-3. Double fluorescence labeling showed HIF-1 alpha positive immunoreactive materials were partly colocalized with NeuN, p53 and Caspase-3 in the injured cerebral cortex. This study showed that HIF-1 alpha siRNA may protect the ischemic-reperfused neurons in vivo via inhibition of HIF-1 alpha, its downstream VEGF and other apoptotic-related proteins such as p53 and Caspase-3 and may have potentials for the early treatment of ischemic cerebral stroke. (C) 2008 Published by Elsevier Inc.