Dose and temporal pattern of estrogen exposure determines neuroprotective outcome in hippocampal neurons: Therapeutic implications

Shuhua Chen, Jon Nilsen, Roberta Diaz Brinton

Research output: Contribution to journalArticlepeer-review

106 Scopus citations


To address controversies of estrogen therapy, in vitro models of perimenopause and prevention vs. treatment modes of 17β-estradiol (E 2) exposure were developed and used to assess the neuroprotective efficacy of E2 against β-amyloid-1-42 (Aβ1-42)- 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 E 2 (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 Aβ1-42-induced neurodegeneration. In prevention vs. treatment simulations, E2 was most effective when present before and during Aβ1-42 insult. In contrast, E2 treatment after Aβ1-42 exposure was ineffective in reversing Aβ-induced degeneration, and exacerbated Aβ1-42-induced cell death when administered after Aβ1-42 insult. We sought to determine the mechanism by which high E2 exacerbated Aβ1-42-induced neurodegeneration by investigating the impact of low vs. high E2 on Aβ1-42-induced dysregulation of calcium homeostasis. Results of these analyses indicated that low E2 significantly prevented Aβ1-42-induced rise in intracellular calcium, whereas high E2 significantly increased intracellular calcium and did not prevent Aβ1-42-induced calcium dysregulation. Therapeutic benefit resulted only from low-dose E2 exposure before, but not after, Aβ1-42-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.

Original languageEnglish (US)
Pages (from-to)5303-5313
Number of pages11
Issue number11
StatePublished - 2006
Externally publishedYes

ASJC Scopus subject areas

  • Endocrinology


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