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Dose and Temporal Pattern of Estrogen Exposure Determines Neuroprotective Outcome in Hippocampal Neurons: Therapeutic Implications

Department of Molecular Pharmacology and Toxicology, University of Southern California, School of Pharmacy Pharmaceutical Sciences Center, Los Angeles, California 90089-9121

Address all correspondence and requests for reprints to: Roberta Diaz Brinton, Ph.D., Department of Molecular Pharmacology and Toxicology, Norris Foundation Laboratory for Neuroscience Research, Pharmaceutical Sciences Center, University of Southern California, 1985 Zonal Avenue, Los Angeles, California 90089-9121. E-mail: rbrinton{at}hsc.usc.edu.

To address controversies of estrogen therapy, in vitro models of perimenopause and prevention vs. treatment modes of 17ß-estradiol (E₂) exposure were developed and used to assess the neuroprotective efficacy of E₂ against ß-amyloid-1–42 (Aß_1–42)-induced neurodegeneration in rat primary hippocampal neurons. Low E₂ (10 ng/ml) exposure exerted neuroprotection in each of the perimenopausal temporal patterns, acute, continuous, and intermittent. In contrast, high E₂ (200 ng/ml) was ineffective at inducing neuroprotection regardless of temporal pattern of exposure. Although high E₂ alone was not toxic, neurons treated with high-dose E₂ resulted in greater Aß_1–42-induced neurodegeneration. In prevention vs. treatment simulations, E₂ was most effective when present before and during Aß_1–42 insult. In contrast, E₂ treatment after Aß_1–42 exposure was ineffective in reversing Aß-induced degeneration, and exacerbated Aß_1–42-induced cell death when administered after Aß_1–42 insult. We sought to determine the mechanism by which high E₂ exacerbated Aß_1–42-induced neurodegeneration by investigating the impact of low vs. high E₂ on Aß_1–42-induced dysregulation of calcium homeostasis. Results of these analyses indicated that low E₂ significantly prevented Aß_1–42-induced rise in intracellular calcium, whereas high E₂ significantly increased intracellular calcium and did not prevent Aß_1–42-induced calcium dysregulation. Therapeutic benefit resulted only from low-dose E₂ exposure before, but not after, Aß_1–42-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. Furthermore, these data are consistent with a healthy cell bias of estrogen benefit.

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