title: Nongenomic antiapoptotic signal transduction by estrogen in cultured cortical neurons.
abstract: 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 17beta-estradiol against acute glutamate toxicity. In the present study, we investigated the mechanism of neuroprotection against apoptosis because acute glutamate toxicity predominantly induced necrosis. 17beta-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 17beta-estradiol. Western blotting analysis demonstrated that treatment with 17beta-estradiol induced the phosphorylation of Akt within 5 min, which was suppressed by pretreatment with LY294002 and ICI182780. Furthermore, 17beta-estradiol induced phosphorylation of the cAMP response element binding protein (CREB) at Ser(133) 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 17beta-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.
authors.affiliation: Department of Neurology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Honda
authors.forename: S
authors.initials: S
authors.lastname: Shimohama
authors.forename: H
authors.initials: H
authors.lastname: Sawada
authors.forename: T
authors.initials: T
authors.lastname: Kihara
authors.forename: T
authors.initials: T
authors.lastname: Nakamizo
authors.forename: H
authors.initials: H
authors.lastname: Shibasaki
authors.forename: A
authors.initials: A
authors.lastname: Akaike
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D017362:Cyclic AMP Response Element-Binding Protein / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000378:metabolism / Q000494:pharmacology*; D015914:Estrogen Replacement Therapy; D005333:Fetus; D018698:Glutamic Acid / Q000378:metabolism; D008593:Menopause / Q000187:drug effects / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D019311:Staurosporine / Q000494:pharmacology
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D004958:Estradiol; D018698:Glutamic Acid; D018696:Neuroprotective Agents; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D012694:Serine; D019311:Staurosporine; C494920:Akt1 protein, rat