The women's health initiative estrogen replacement therapy is neurotrophic and neuroprotective.
The current study investigated the neurotrophic and neuroprotective action of the complex formulation of conjugated equine estrogens (CEEs), the most frequently prescribed estrogen replacement therapy in the United States and the estrogen replacement therapy of the Women's Health Initiative. Morphologic analyses demonstrated that CEEs significantly increased neuronal outgrowth in hippocampal, basal forebrain, occipital, parietal and frontal cortex neurons. Dose-response analyses indicated that the lowest effective concentration of CEEs exerted the maximal neurotrophic effect with greatest potency occurring in hippocampal and occipital cortex neurons. CEES induced highly significant neuroprotection against beta amyloid(25-35), hydrogen peroxide and glutamate-induced toxicity. Rank order of potency and magnitude of CEE-induced neuroprotection in the brain regions investigated was hippocampal neurons > basal forebrain neurons > cortical neurons. In hippocampal neurons pre-exposed to beta amyloid(25-35), CEEs halted Abeta(25-35)-induced cell death and protected surviving neurons from further cell death induced by Abeta(25-35). Because CEEs are the estrogen replacement therapy of the Women's Health Initiative, results of the current study could provide cellular mechanisms for understanding effects of CEEs on cognitive function and risk of Alzheimer's disease derived from this prospective clinical trial.
Diaz Brinton
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Department of Molecular Pharmacology and Toxicology and the Program in Neuroscience, University of Southern California, Pharmaceutical Sciences Center, 1985 Zonal Avenue, Los Angeles, CA 90033, USA. rbrinton@hsc.usc.edu
Chen
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Montoya
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Hsieh
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Minaya
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Kim
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Chu
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D000255:Adenosine Triphosphate / Q000378:metabolism; D000375:Aging / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000166:cytology; D001923:Brain Chemistry / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D015914:Estrogen Replacement Therapy; D004966:Estrogens, Conjugated (USP) / Q000494:pharmacology*; D018698:Glutamic Acid / Q000494:pharmacology; D006736:Horses; D006861:Hydrogen Peroxide / Q000633:toxicity; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008568:Memory / Q000187:drug effects; D009420:Nervous System / Q000187:drug effects* / Q000254:growth & development; D009474:Neurons / Q000187:drug effects* / Q000648:ultrastructure; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats
D016229:Amyloid beta-Peptides; D004966:Estrogens, Conjugated (USP); D018696:Neuroprotective Agents; D010446:Peptide Fragments; C074636:amyloid beta-protein (25-35); D018698:Glutamic Acid; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; D007770:L-Lactate Dehydrogenase