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Submitted on April 17, 2006
Accepted on August 8, 2006
Department of Molecular Pharmacology & Toxicology, University of Southern California, School of Pharmacy Pharmaceutical Sciences Center, 1985 Zonal Avenue, Los Angeles, CA 90089-9121
* To whom correspondence should be addressed. E-mail: rbrinton{at}hsc.usc.edu.
To address controversies of estrogen therapy, in vitro models of perimenopause and prevention vs. treatment modes of 17
-estradiol (E2) exposure were developed and used to assess the neuroprotective efficacy of E2 against beta-amyloid-1-42 (A1-42)-induced neurodegeneration in rat primary hippocampal neurons. Low E2 (10ng/ml) exposure exerted neuroprotection in each of the perimenopausal temporal patterns, acute, continuous and intermittent. In contrast, high E2 (200ng/ml) was ineffective at inducing neuroprotection regardless of temporal pattern of exposure. While high E2 alone was not toxic, neurons treated with high dose E2 resulted in greater A1-42-induced neurodegeneration. In prevention vs. treatment simulations, E2 was most effective when present before and during Ab1-42 insult. In contrast, E2 treatment following A1-42 exposure was ineffective in reversing A-induced degeneration and exacerbated A1-42-induced cell death when administered after A1-42 insult. We sought to determine the mechanism by which high E2 exacerbated A1-42-induced neurodegeneration by investigating the impact of low vs. high E2 on Ab1-42-induced dysregulation of calcium homeostasis. Results of these analyses indicated that low E2 significantly prevented A1-42-induced rise in intracellular calcium whereas high E2 significantly increased intracellular calcium and did not prevent A1-42-induced calcium dysregulation. Therapeutic benefit resulted only from low dose E2 exposure before, but not following, A1-42-induced neurodegeneration. These data are relevant to impact of perimenopausal E2 exposure on protection against neurodegenerative insults and the use of estrogen therapy to prevent vs. treat Alzheimer's disease. Further, these data are consistent with a healthy cell bias of estrogen benefit.
-estradiol •
Estrogen therapy •
Hormone therapy •
Alzheimer's disease •
menopause •
perimenopause
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