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, ROCÍO; KOLLIKER FRES, RODOLFO; GARCÍA-SEGURA, LUIS MIGUEL; CAPANI, FRANCISCO

Buenos Aires

Congreso; 2do. SIMPOSIO FRANCO-ARGENTINO DE NEUROCIENCIAS; 2012

SOCIEDAD ARGENTINA DE INVESTIGACION EN NEUROCIENCIAS y la SOCIEDAD DE NEUROCIENCIAS EN FRANCIA

Perinatal asphyxia (PA) is associated with increased short-term mortality andphychiatric and neurological disorders.We have previously shown that differentneurodegenerative markers can be observed in CA1 hippocampal area of 4-months-oldasphyctic rats.We have also shown that a late treatment with 17b estradiol (daily dose of250 μg/kg for 3 days) is able to revert some of the alterations observed in the adultasphyctic rats.The aim of this work is to study the signaling pathway involved in thereversion of the alterations by PA due to estrogenic treatment.By means of Western blotanalyses, we demonstrated that asphyctic animals treated with vehicle (PA-Vhi) showedno differences in estrogen receptors (ER),membrane receptor GPR30 and insulin-likegrowth factor-I receptor (IGF-IR) when compared with control groups.However,estradiollate treatment induced an increase in the levels of ERα and IGF-IRB in asphyctic animals(PA-17b) in comparison to CTL-Vhi, CTL-17b and PA-Vhi. Due to IGF-IR and ERa interactin neuroprotective events,we studied the IGF-I signaling pathway.PA-Vhi animals showeda decrease in the activation of phosphoinositide 3-kinase (PI3K) and serine/threonineprotein kinase (Akt) and an increase in the glycogen synthase kinase 3 (GSK-3)activity.The activation of GSK3 could redirect b-catenin in proteosome pathway,which isobserved in PA-Vhi animals.Estradiol late treatment induced the activation of PI3Kpathway in PA-17b animals,allowing an increase in the activation of Akt and the inhibitionof GSK3 respect to PA-Vhi animals.The inhibition of GSK3 allows nuclear translocationand transcriptional activity of b-catenin observed in PA-17b animals.The signaling pathwayactivated by estradiol promotes a significant increase in Bcl-2/Bax ratio respect to PA-Vhigroup.Taking together, our data suggest that the interaction between ERa and IGF-IR,withthe subsequent downstream activation, underlies the beneficial effects of estradiol in latetreatment of PA.