| 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 | K Honda, S Shimohama, H Sawada, T Kihara, T Nakamizo, H Shibasaki, A Akaike
(Affiliation: Department of Neurology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan.)
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| Journal | Journal of neuroscience research
(J Neurosci Res)
Vol. 64
Issue 5
Pg. 466-75
(Jun 1 2001)
ISSN: 0360-4012 United States |
| PMID | 11391701
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
| Copyright | Copyright 2001 Wiley-Liss, Inc. |
| Chemical References |
- Cyclic AMP Response Element-Binding Protein
- Enzyme Inhibitors
- Neuroprotective Agents
- Proto-Oncogene Proteins
- Proto-Oncogene Proteins c-bcl-2
- Estradiol
- Serine
- Glutamic Acid
- Staurosporine
- 1-Phosphatidylinositol 3-Kinase
- Akt1 protein, rat
- Proto-Oncogene Proteins c-akt
- Protein-Serine-Threonine Kinases
|
| Topics |
- 1-Phosphatidylinositol 3-Kinase
(drug effects, metabolism)
- Alzheimer Disease
(drug therapy, physiopathology, prevention & control)
- Animals
- Apoptosis
(drug effects, physiology)
- Cells, Cultured
(drug effects, metabolism, pathology)
- Cerebral Cortex
(drug effects, metabolism, physiopathology)
- Cyclic AMP Response Element-Binding Protein
(drug effects, metabolism)
- Enzyme Inhibitors
(pharmacology)
- Estradiol
(metabolism, pharmacology)
- Estrogen Replacement Therapy
- Fetus
- Glutamic Acid
(metabolism)
- Menopause
(drug effects, metabolism)
- Nerve Degeneration
(chemically induced, physiopathology, prevention & control)
- Neurons
(drug effects, metabolism, pathology)
- Neuroprotective Agents
(pharmacology)
- Phosphorylation
(drug effects)
- Protein-Serine-Threonine Kinases
- Proto-Oncogene Proteins
(drug effects, metabolism)
- Proto-Oncogene Proteins c-akt
- Proto-Oncogene Proteins c-bcl-2
(drug effects, metabolism)
- Rats
- Rats, Sprague-Dawley
- Serine
(metabolism)
- Signal Transduction
(drug effects, physiology)
- Staurosporine
(pharmacology)
|
