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 17beta-estradiol (E(2)) exposure were developed and used to assess the neuroprotective efficacy of E(2) against beta-amyloid-1-42 (Abeta(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 Abeta(1-42)-induced neurodegeneration. In prevention vs. treatment simulations, E(2) was most effective when present before and during Abeta(1-42) insult. In contrast, E(2) treatment after Abeta(1-42) exposure was ineffective in reversing Abeta-induced degeneration, and exacerbated Abeta(1-42)-induced cell death when administered after Abeta(1-42) insult. We sought to determine the mechanism by which high E(2) exacerbated Abeta(1-42)-induced neurodegeneration by investigating the impact of low vs. high E(2) on Abeta(1-42)-induced dysregulation of calcium homeostasis. Results of these analyses indicated that low E(2) significantly prevented Abeta(1-42)-induced rise in intracellular calcium, whereas high E(2) significantly increased intracellular calcium and did not prevent Abeta(1-42)-induced calcium dysregulation. Therapeutic benefit resulted only from low-dose E(2) exposure before, but not after, Abeta(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.
Chen
Shuhua
S
Department of Molecular Pharmacology and Toxicology, University of Southern California, 1985 Zonal Avenue, Los Angeles, California 90089-9121, USA.
Nilsen
Jon
J
Brinton
Roberta Diaz
RD
D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000633:toxicity; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D006624:Hippocampus / Q000187:drug effects*; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010446:Peptide Fragments / Q000633:toxicity; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley
D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D004958:Estradiol; D017258:Medroxyprogesterone Acetate; D002118:Calcium