Nongenomic antiapoptotic signal transduction by estrogen in cultured cortical neurons

Estrogen replacement therapy in menopausal women has been suggested to be beneficial in preventing the progression of cognitive impairment in Alzheimer disease. We demonstrated previously that the phosphatidylinositol 3‐kinase (PI3‐K)/Akt signal transduction pathway plays a pivotal role on the neuroprotection provided by 17β‐estradiol against acute glutamate toxicity. In the present study, we investigated the mechanism of neuroprotection against apoptosis because acute glutamate toxicity predominantly induced necrosis. 17β‐estradiol provided neuroprotection against apoptosis induced by staurosporine. This neuroprotection was inhibited by pretreatment with a PI3‐K inhibitor, LY294002. An estrogen receptor specific antagonist, ICI182780, also suppressed the neuroprotection provided by 17β‐estradiol. Western blotting analysis demonstrated that treatment with 17β‐estradiol induced the phosphorylation of Akt within 5 min, which was suppressed by pretreatment with LY294002 and ICI182780. Furthermore, 17β‐estradiol induced phosphorylation of the cAMP response element binding protein (CREB) at Ser133 within 15 min and then upregulated Bcl‐2 in a PI3‐K/Akt‐dependent manner. Because CREB is known to be a transcription factor for Bcl‐2, these results suggest that 17β‐estradiol exerts its antiapoptotic effects by CREB phosphorylation and Bcl‐2 upregulation via nongenomic activation of the PI3‐K/Akt pathway in cultured cortical neurons. J. Neurosci. Res. 64:466–475, 2001. © 2001 Wiley‐Liss, Inc.