Phosphatidylinositol 3-kinase mediates neuroprotection by estrogen in cultured cortical neurons.
It has been shown that estrogen replacement in menopausal women is effective in slowing down the progression of cognitive impairment in Alzheimer's disease. Although recent studies have demonstrated the neuroprotective effects of estrogen, the precise mechanism of neuroprotection has not been elucidated. 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 cortical neurons. Pretreatment with 10 nM 17beta-estradiol significantly attenuated the glutamate-induced toxicity. This neuroprotective effect of 17beta-estradiol was blocked by co-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 ICI182780, a specific estrogen receptor antagonist, also blocked the neuroprotection. Immunoblotting assay revealed that treatment with 17beta-estradiol induced the phosphorylation of Akt/PKB, an effector immediately downstream of PI3-K. These results suggest that PI3-K mediates the neuroprotective effect of 17beta-estradiol against glutamate-induced neurotoxicity.
Honda
K
K
Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Sawada
H
H
Kihara
T
T
Urushitani
M
M
Nakamizo
T
T
Akaike
A
A
Shimohama
S
S
D000818:Animals; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D000077267:Fulvestrant; D018698:Glutamic Acid / Q000633:toxicity; D009025:Morpholines / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley
D002867:Chromones; D004791:Enzyme Inhibitors; D004958:Estradiol; D004965:Estrogen Antagonists; D004967:Estrogens; D018691:Excitatory Amino Acid Antagonists; D005419:Flavonoids; D000077267:Fulvestrant; D018698:Glutamic Acid; D009025:Morpholines; D018696:Neuroprotective Agents; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one