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

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