Phosphatidylinositol 3-kinase mediates neuroprotection by estrogen in cultured cortical neurons

It has been shown that estrogen replacement in menopausal women is effectiv e in slowing down the progression of cognitive impairment in Alzheimer's di sease. Although recent studies have demonstrated the neuroprotective effect s of estrogen, the precise mechanism of neuroprotection has not been elucid ated. In the present study, we show that the phosphatidylinositol 3-kinase (PI3-K) cascade is involved in the neuroprotective mechanism stimulated by estrogen. Exposure to glutamate reduced the viability of rat primary cortic al neurons. Pretreatment with 10 nM 17 beta-estradiol significantly attenua ted the glutamate-induced toxicity. This neuroprotective effect of 17 beta- estradiol was blocked by cc-administration with LY294002, a selective PI3-K inhibitor, but not by co-administration with PD98059, a selective mitogen activated protein kinase kinase inhibitor. Pretreatment with \C\182780, a s pecific estrogen receptor antagonist, also blocked the neuroprotection. Imm unoblotting assay revealed that treatment with 17 beta-estradiol induced th e phosphorylation of Akt/PKB, an effector immediately downstream of PI3-K. These results suggest that PI3-K mediates the neuroprotective effect of 17 beta-estradiol against glutamate-induced neurotoxicity. (C) 2000 Wiley-Liss , Inc.