Dose and temporal pattern of estrogen exposure determines neuroprotective outcome in hippocampal neurons: therapeutic implications. Endocrinology

To address controversies of estrogen therapy, in vitromodels of perimenopause and prevention vs. treatment modes of 17-estradiol (E2) exposure were developed and used to assess the neuroprotective efficacy of E2 against -amyloid-1–42 (A1–42)-induced neurodegeneration in rat primary hip-pocampal neurons. Low E2 (10 ng/ml) exposure exerted neu-roprotection in each of the perimenopausal temporal pat-terns, acute, continuous, and intermittent. Incontrast, highE2 (200 ng/ml) was ineffective at inducing neuroprotection re-gardless of temporal pattern of exposure. Although high E2 alone was not toxic, neurons treated with high-dose E2 re-sulted in greater A1–42-induced neurodegeneration. In pre-vention vs. treatment simulations, E2 wasmost effectivewhen present before and during A1–42 insult. In contrast, E2 treat-ment after A1–42 exposure was ineffective in reversing A