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Institute of Molecular Medicine and Genetics, Program in Developmental Neurobiology, and Department of Neurology, Medical College of Georgia, Augusta, Georgia 30912
Address all correspondence and requests for reprints to: Dr. Darrell W. Brann, Institute of Molecular Medicine and Genetics, Program in Developmental Neurobiology, 1120 15th Street, Medical College of Georgia, Augusta, Georgia 30912. E-mail: dbrann{at}mail.mcg.edu.
17ß-Estradiol (E2) and selective estrogen receptor modulators (SERMs), such as tamoxifen, mediate numerous effects in the brain, including neurosecretion, neuroprotection, and the induction of synaptic plasticity. Astrocytes, the most abundant cell type in the brain, influence many of these same functions and thus may represent a mediator of estrogen action. The present study examined the regulatory effect and underlying cell signaling mechanisms of E2-induced release of neurotropic growth factors from primary rat cortical astrocyte cultures. The results revealed that E2 (0.5, 1, and 10 nM) and tamoxifen (1 µM) increased both the expression and release of the neuroprotective cytokines, TGF-ß1 and TGF-ß2 (TGF-ß), from cortical astrocytes. The stimulatory effect of E2 was attenuated by the estrogen receptor (ER) antagonist, ICI182,780, suggesting ER dependency. The effect of E2 also appeared to involve mediation by the phosphotidylinositol 3-kinase (PI3K)/Akt signaling pathway, because E2 rapidly induced Akt phosphorylation, and pharmacological or molecular inhibition of the PI3K/Akt pathway prevented E2-induced release of TGF-ß. Additionally, the membrane-impermeant conjugate, E2-BSA, stimulated the release of TGF-ß, suggesting the potential involvement of a membrane-bound ER. Finally, E2, tamoxifen, and E2-BSA were shown to protect neuronal-astrocyte cocultures from camptothecin-induced neuronal cell death, effects that were attenuated by ICI182,780, Akt inhibition, or TGF-ß immunoneutralization. As a whole, these studies suggest that E2 induction of TGF-ß release from cortical astrocytes could provide a mechanism of neuroprotection, and that E2 stimulation of TGF-ß expression and release from astrocytes occurs via an ER-dependent mechanism involving mediation by the PI3K/Akt signaling pathway.
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