Activation of PI3K/Akt/GSK3 signaling pathway by estradiol therapy in adulthood is associated with the reversion of neurodegenerative damage caused by perinatal asphyxia

SARACENO, GUSTAVO EZEQUIEL; BELLINI, MARÍA JOSÉ; ROMERO, JUAN IGNACIO; HOLUBIEC, MARIANA; GALEANO, PABLO; CASTILLA LOZANO, MARÍA DEL ROCIO; KÖLLIKER FRERS, RODOLFO ALBERTO; GARCIA-SEGURA, LUIS MIGUEL; CAPANI, FRANCISCO

Buenos Aires

Congreso; II Simposio Franco-Argentino de Neurociencias; 2012

Sociedad Argentina de Investigación en Neurociencias

Perinatal asphyxia (PA) is associated with increased short-term mortality and phychiatric and neurological disorders. We have previously shown that different neurodegenerative markers can be observed in CA1 hippocampal area of 4-months-old asphyctic rats. We have also shown that a late treatment with 17 beta estradiol (daily dose of 250 µg/kg for 3 days) is able to revert some of the alterations observed in the adult asphyctic rats. The aim of this work is to study the signaling pathway involved in the reversion of the alterations by PA due to estrogenic treatment. By means of Western blot analyses, we demonstrated that asphyctic animals treated with vehicle (PA-Vhi) showed no differences in estrogen receptors (ER), membrane receptor GPR30 and insulin-like growth factor-I receptor (IGF-IR) when compared with control groups. However, estradiol late treatment induced an increase in the levels of ERalpha and IGF-IRB in asphyctic animals (PA-17beta) in comparison to CTL-Vhi, CTL-17beta and PA-Vhi. Due to IGF-IR and ERalpha interact in neuroprotective events, we studied the IGF-I signaling pathway. PA-Vhi animals showed a decrease in the activation of phosphoinositide 3-kinase (PI3K) and serine/threonine protein kinase (Akt) and an increase in the glycogen synthase kinase 3 (GSK-3) activity. The activation of GSK3 could redirect beta-catenin in proteosome pathway, which is observed in PA-Vhi animals. Estradiol late treatment induced the activation of PI3K pathway in PA-17beta animals, allowing an increase in the activation of Akt and the inhibition of GSK3 respect to PA-Vhi animals. The inhibition of GSK3 allows nuclear translocation and transcriptional activity of beta-catenin observed in PA-17beta animals. The signaling pathway activated by estradiol promotes a significant increase in Bcl-2/Bax ratio respect to PA-Vhi group. Taking together, our data suggest that the interaction between ERalpha and IGF-IR, with the subsequent downstream activation, underlies the beneficial effects of estradiol in late treatment of PA.