Toran-Allerand C Dominique, Tinnikov Alexander A, Singh Ravinder J, Nethrapalli Imam S
Department of Anatomy and Cell Biology, Columbia University College of Physicians and Surgeons, 650 West 168th Street, Black Building, Room 1615, New York, New York 10032, USA.
Endocrinology. 2005 Sep;146(9):3843-50. doi: 10.1210/en.2004-1616. Epub 2005 Jun 9.
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.
雌激素17β-雌二醇在一生中对大脑都有深远影响，而天然旋光异构体17α-雌二醇通常被认为活性较低，因为它与雌激素受体的结合不太紧密。相反，最近在大脑中的研究表明，17α-雌二醇能引发丝裂原活化蛋白激酶/细胞外信号调节激酶（MAPK/ERK）和磷脂酰肌醇3-激酶-蛋白激酶B（PI3K-Akt）信号通路的快速持续激活；在缺血性中风、氧化应激后以及患有阿尔茨海默病的转基因小鼠中具有神经保护作用；并影响空间记忆和海马依赖性突触可塑性。本研究测量了大脑中17α-雌二醇的内源性含量，并进一步阐明了其作用和动力学。在此我们报告：1）通过液相色谱/串联质谱法测定，出生后及成年小鼠大脑和肾上腺中17α-雌二醇及其前体雌酮的内源性水平在两性中均显著升高；2）17α-雌二醇和17β-雌二醇与雌激素受体的结合亲和力相似；3）17α-雌二醇能反式激活雌激素反应报告基因；4）与17β-雌二醇不同，17α-雌二醇不与甲胎蛋白或性激素结合球蛋白（SHBG）结合，甲胎蛋白和SHBG分别是发育中的啮齿动物和灵长类动物的雌激素结合血浆蛋白。在去势或去势/肾上腺切除小鼠的大脑中也发现了17α-雌二醇，这支持了17α-雌二醇在大脑中局部合成的假说。这些发现挑战了17α-雌二醇没有生物学意义的观点，并表明17α-雌二醇及其选择性受体ER-X不是经典激素/受体内分泌系统的一部分，而是在发育中和成年大脑中具有重要自分泌/旁分泌功能的系统的一部分。17α-雌二醇可能对更年期激素替代策略以及阿尔茨海默病和缺血性中风等神经退行性疾病的治疗具有巨大意义。
