HIF-1α inhibition ameliorates neonatal brain injury in a rat pup hypoxic–ischemic model

Abstract

Hypoxia-inducible factor-1alpha (HIF-1α) has been considered as a regulator of both prosurvival and prodeath pathways in the nervous system. The present study was designed to elucidate the role of HIF-1α in neonatal hypoxic–ischemic (HI) brain injury. Rice–Vannucci model of neonatal hypoxic–ischemic brain injury was used in seven-day-old rats, by subjecting unilateral carotid artery ligation followed by 2 h of hypoxia (8% O2 at 37 °C). HIF-1α activity was inhibited by 2-methoxyestradiol (2ME2) and enhanced by dimethyloxalylglycine (DMOG). Results showed that 2ME2 exhibited dose-dependent neuroprotection by decreasing infarct volume and reducing brain edema at 48 h post HI. The neuroprotection was lost when 2ME2 was administered 3 h post HI. HIF-1α upregulation by DMOG increased the permeability of the BBB and brain edema compared with HI group. 2ME2 attenuated the increase in HIF-1α and VEGF 24 h after HI. 2ME2 also had a long-term effect of protecting against the loss of brain tissue. The study showed that the early inhibition of HIF-1α acutely after injury provided neuroprotection after neonatal hypoxia–ischemia which was associated with preservation of BBB integrity, attenuation of brain edema, and neuronal death.

Keywords

• Brain edema
• Hypoxia inducible factor
• Neonatal hypoxia ischemia
• Neuroprotection