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Submitted on December 15, 2004
Accepted on May 27, 2005
-ESTRADIOL: A BRAIN ACTIVE ESTROGEN?
Departments of Anatomy & Cell Biology, Obstetrics & Gynecology, (C.D.T-A., A.A.T., I.S.N.) and Neurology (C.D.T-A.) and the Centers for Neurobiology and Behavior and Reproductive Sciences (C.D.T-A., A.A.T., I.S.N.), Columbia University College of Physicians & Surgeons, New York, New York 10032, and Department of Laboratory Medicine and Pathology, Mayo Clinic and Foundation (R.J.S.), Rochester, MN 55905, U.S.A.
* To whom correspondence should be addressed. E-mail: cdt2{at}columbia.edu.
The estrogen 17
-estradiol has profound effects on the brain throughout life, while 17
-estradiol, the natural optical isomer, is generally considered less active, because it binds less avidly to estrogen receptors. On the contrary, recent studies in the brain document that 17-estradiol (a) elicits rapid and sustained activation of the MAP/ERK kinase and PI3K-Akt signaling pathways, (b) is neuroprotective, following an ischemic stroke and oxidative stress, and in transgenic mice with Alzheimer's disease, and (c) influences spatial memory and hippocampal-dependent synaptic plasticity. The present study measured the endogenous content of 17-estradiol in the brain and further clarified its actions and kinetics. Here we report that (i) endogenous levels of 17-estradiol and its precursor estrone are significantly elevated in the postnatal and adult mouse brain and adrenal gland of both sexes, as determined by liquid chromatography/tandem mass spectrometry (LC-MS/MS); (ii) 17-estradiol and 17-estradiol bind estrogen receptors with similar binding affinities; (iii) 17-estradiol transactivates an estrogen-responsive reporter gene, and (iv) unlike 17-estradiol, 17-estradiol does not bind -fetoprotein or sex hormone binding globulin, the estrogen-binding plasma proteins of the developing rodent and primate, respectively. 17-estradiol was also found in the brains of gonadectomized or gonadectomized/adrenalectomized mice, supporting the hypothesis that 17-estradiol is locally synthesized in the brain. These findings challenge the view that 17-estradiol is without biological significance and suggest that 17-estradiol and its selective receptor "ER-X" are not part of a classical hormone/receptor endocrine system, but of a system with important autocrine/paracrine functions in the developing and adult brain. 17-estradiol may have enormous implications for hormone replacement strategies at the menopause and in the treatment of such neurodegenerative disorders as Alzheimer's disease and ischemic stroke.
-estradiol •
17-estradiol •
estrone •
"ER-X" •
brain •
liquid chromatography-tandem mass spectrometry
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