Role of hypoxia-inducible factor-1 in hypoxia-induced ischemic tolerance in neonatal rat brain

Hypoxia-inducible factor-1 (HIF-1) is a heterodimer composed of HIF-1 alpha and HIF-1 beta protein subunits. This transcription factor is essential fo r the activation of hypoxia-inducible genes like erythropoietin, some gluco se transporters, the glycolytic enzymes, and vascular endothelial growth fa ctor. Because HIF-1 activation may promote cell survival in hypoxic tissues , we studied the effect of hypoxic preconditioning on HIF-1 expression in n eonatal rat brain. Hypoxic preconditioning (8% O-2 for 3 hours), a treatmen t known to protect the newborn rat brain against hypoxic-ischemic injury, m arkedly increased HIF-1 alpha and HIF-1 beta expression. To support the rol e of HIF-1 in protective preconditioning, we also studied the effect of two other known HIF-1 inducers, cobalt chloride (CoCl2) and desferrioxamine (D FX), on HIF-1 expression and neuroprotection in newborn brain. HIF-1 alpha and HIF-1 beta protein levels were markedly increased after intraperitoneal injection of CoCl2 (60 mg/kg) and moderately increased after intraperitone al injection of DDC (200 mg/kg) 1 to 3 hours after the injections. Precondi tioning with CoCl2 or DFX 24 hours before hypoxia-ischemia afforded 75 and 56% brain protection, respectively, compared with that in vehicle-injected littermate controls. Thus, HIF-1 activation could contribute to protective brain preconditioning, which could be used in high-risk deliveries and othe r clinical situations.