Hypoxic preconditioning in neonatal rat brain involves regulation of excitatory amino acid transporter 2 and estrogen receptor alpha

Exposure of the brain to a sublethal insult can protect against a subsequent brain injury. Hypoxic preconditioning induces tolerance to hypoxic-ischemic injury in neonatal rat brain and is associated with changes in gene and protein expression. To study the involvement of excitatory amino acid transporters (EAAT1 and EAAT2) and estrogen receptors (ERα and ERβ) in neonatal hypoxia-induced ischemic tolerance, we examined changes in expression of these proteins in the cortex, hippocampus and striatum of newborn rats at different time points after exposure to sublethal hypoxia (8% O2, 3 h). Preconditioning with hypoxia 24 h before hypoxia-ischemia afforded marked brain protection compared with littermate control animals as determined by morphological assessment. Immunoblot analysis showed that EAAT2 and ERα were significantly increased by 55% and 49%, respectively, in cortex at 24 h after hypoxic-preconditioning. Surprisingly, at the same time point, a significant decrease of EAAT2 by 48% in striatum was observed. In contrast, hypoxic preconditioning had no effect on the levels of EAAT1 and ERβ in any of the brain regions studied at any of the time points analyzed. The similar pattern of changes in EAAT2 and ERα levels suggests that ERα might interact with EAAT2 in producing preconditioning. The endogenous molecular mechanisms modulated by hypoxia preconditioning may contribute to the development of hypoxia-induced ischemic tolerance, and may provide novel therapeutic targets for the treatment of cerebral ischemia.