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17alpha-estradiol: a brain-active estrogen?

The estrogen 17beta-estradiol has profound effects on the brain throughout life, whereas 17alpha-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 17alpha-estradiol elicits rapid and sustained activation of the MAPK/ ERK and phosphatidylinositol 3-kinase-Akt signaling pathways; is neuroprotective, after an ischemic stroke and oxidative stress, and in transgenic mice with Alzheimer's disease; and influences spatial memory and hippocampal-dependent synaptic plasticity. The present study measured the endogenous content of 17alpha-estradiol in the brain and further clarified its actions and kinetics. Here we report that: 1) endogenous levels of 17alpha-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; 2) 17alpha-estradiol and 17beta-estradiol bind estrogen receptors with similar binding affinities; 3) 17alpha-estradiol transactivates an estrogen-responsive reporter gene; and 4) unlike 17beta-estradiol, 17alpha-estradiol does not bind alpha-fetoprotein or SHBG, the estrogen-binding plasma proteins of the developing rodent and primate, respectively. 17alpha-Estradiol was also found in the brains of gonadectomized or gonadectomized/adrenalectomized mice, supporting the hypothesis that 17alpha-estradiol is locally synthesized in the brain. These findings challenge the view that 17alpha-estradiol is without biological significance and suggest that 17alpha-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. 17alpha-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.[1]

References

  1. 17alpha-estradiol: a brain-active estrogen? Toran-Allerand, C.D., Tinnikov, A.A., Singh, R.J., Nethrapalli, I.S. Endocrinology (2005) [Pubmed]
 
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