104 Protective Effect of 17ß-Estradiol Against Oxygen Induced Neurodegeneration in the Developing Rat Brain

Neurologic morbidity often occurs in survivors of premature birth. Clinical studies have identified hyperoxia as a risk factor for cerebral palsy. Short exposure to high oxygen levels can trigger neurodegeneration in the developing rat brain. Toxicity of oxygen is associated with inactivation of intracellular proteins that promote survival and increased expression of the proapoptotic Fas-receptor. In this animal model of neonatal brain damage we tested Estradiol against the detrimental effect of oxygen. This hormone has neuroprotective properties that result from activation of estrogen receptors and cross-talk with signaling pathways that are activated by neurotrophins. 6-day old rats were subjected to 80% oxygen and Estradiol was co-administered (600 µg/kg i.p.) at beginning of exposure. Pups were sacrificed at defined time points and brains were either examined histologically to visualize degenerating cells or were snap frozen for molecular studies. Estradiol conferred significant protection against oxygen-induced neurodegeneration. To explore further possible molecular mechanisms, we investigated the impact of Estradiol on the expression of the death receptor Fas and Fas-Ligand. Following hyperoxia for 12 and 24h increased levels of Fas and Fas-Ligand mRNA were found. In the presence of Estradiol mRNA levels of the Fas-system were reduced. Immunoblot analysis on two signaling pathways (MAPK, PI3-kinase) that control neuronal survival, revealed that co-administration of Estradiol counteracts inactivation of the two key players ERK1/2 and AKT. The downregulation in the expression of Fas and Fas-Ligand and increased levels of active forms of ERK1/2 and AKT may represent important mechanisms that lead to survival of neuronal cells. Our results suggest that Estradiol might be suitable as a neuroprotective agent in preterm and term infants who need to be exposed to oxygen. Especially in preterm infants, who are prematurely deprived of maternal intrauterine estrogen, maintaining physiological plasma levels of 17ß-Estradiol may help to protect from potentially neurotoxic triggers.