Estrogen receptor-mediated neuroprotection from oxidative stress requires activation of the mitogen-activated protein kinase pathway.
It is well documented that estrogen mediates responses by both genomic and nongenomic mechanisms, both of which are important for cell survival. Because direct evidence showing that the estrogen receptors (ERs) alpha and/or beta can activate rapid signaling that may mediate neuroprotection is lacking, the hippocampal-derived cell line, HT22, was stably transfected with ERalpha (HTERalpha), ERbeta (HTERbeta), or a mutated form of ERalpha (HTERalphaHE27), which lacks the ability to mediate ER element-mediated transcription. Treatment of HT22, HTERalpha, HTERbeta, and HTERalphaHE27 cells with glutamate (5 mM) resulted in a significant decrease in cell viability. Pretreatment for 15 min with 10 nM 17beta-estradiol resulted in a 50% increase in the number of living cells in HTERalpha and HTERbeta cells but not in HT22 cells. The ER antagonist ICI 182,780 and the MEK inhibitor PD98059 prevented 17beta-estradiol-mediated protection. In HTERalphaHE27 cells, 17beta-estradiol rapidly phosphorylated ERK2 (within 15 min), in the absence of estrogen response element-mediated transcription. Treatment of HTERalphaHE27 cells with 10 nM 17beta-estradiol partially reversed the cell death produced by glutamate treatment. This study demonstrates that activation of either ERalpha or ERbeta can result in neuroprotection and that activation of the MAPK pathway is an important part of the neuroprotective mechanism.
Mize
Amy L
AL
Department of Pharmacology, University of Washington, Seattle, Washington 98195, USA.
Shapiro
Robert A
RA
Dorsa
Daniel M
DM
D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D005419:Flavonoids / Q000494:pharmacology; D000077267:Fulvestrant; D018698:Glutamic Acid / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009154:Mutation; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress; D051381:Rats; D011960:Receptors, Estrogen / Q000235:genetics / Q000502:physiology*; D014162:Transfection
D004791:Enzyme Inhibitors; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D005419:Flavonoids; D018696:Neuroprotective Agents; D011960:Receptors, Estrogen; D000077267:Fulvestrant; D018698:Glutamic Acid; D004958:Estradiol; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one