Contribution of estrogen receptors α and β to the effects of estradiol in the brain
Contribution of estrogen receptors α and β to the effects of estradiol in the brain
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DOI：
10.1016/j.jsbmb.2007.09.011
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发表时间：
2008-02-01
影响因子：
4.1
通讯作者：
Di Paolo, T.
中科院分区：
文献类型：
--
作者：
Morissette, M.;Le Saux, M.;Di Paolo, T.
临床和实验研究表明雌激素在大脑中的调节作用，并表明其在精神和神经退行性疾病中的有益作用。雌激素受体ER α和ER β存在于大脑中，它们的靶向作用可以带来选择性并降低癌症风险。雌激素受体在雌二醇对多巴胺、阿片和谷氨酸神经传递的影响中的意义。ER α激动剂PPT显示为雌二醇，以调节卵巢切除大鼠皮质和纹状体中的海马NMDA受体和AMPA受体，而ER β激动剂DPN无活性。纹状体DPN活性表明ER β参与了卵巢切除大鼠D2受体和转运蛋白的雌二醇调节，并得到了ER β敲除（ERKO β）小鼠中雌二醇缺乏作用的支持。雌激素受体α和β激动剂调节纹状体前脑啡肽原（PPE）基因表达在卵巢切除大鼠。在雄性小鼠中，PPT保护纹状体多巴胺免受MPTP毒性;这涉及Akt/GSK 3 β信号传导和凋亡调节因子Bcl 2和Bad。这表明ER α在纹状体多巴胺神经保护中的作用。ERKO α小鼠更容易受到MPTP毒性的影响，并且不受雌二醇的保护; ERKO β小鼠的差异更微妙。这些结果表明ER特异性激动剂对脑的治疗潜力。(c)2007爱思唯尔有限公司保留所有权利。
Clinical and experimental studies show a modulatory role of estrogens in the brain and suggest their beneficial action in mental and neurodegenerative diseases. The estrogen receptors ER alpha and ER beta are present in the brain and their targeting could bring selectivity and reduced risk of cancer. Implication of ERs in the effect of estradiol on dopamine, opiate and glutamate neurotransmission is reviewed. The ERa agonist, PPT, is shown as estradiol to modulate hippocampal NMDA receptors and AMPA receptors in cortex and striatum of ovariectomized rats whereas the ER beta agonist DPN is inactive. Striatal DPN activity suggests implication of ER beta in estradiol modulation of D2 receptors and transporters in ovariectomized rats and is supported by the lack of effect of estradiol in ER beta knockout (ERKO beta) mice. Both ER alpha and ER beta agonists modulate striatal preproenkephalin (PPE) gene expression in ovariectomized rats. In male mice PPT protects against MPTP toxicity to striatal dopamine; this implicates Akt/GSK3 beta signaling and the apoptotic regulators Bcl2 and Bad. This suggests a role for ER alpha in striatal dopamine neuroprotection. ERKO alpha mice are more susceptible to MPTP toxicity and not protected by estradiol; differences in ERKO beta mice are subtler. These results suggest therapeutic potential for the brain of ER specific agonists. (c) 2007 Elsevier Ltd. All rights reserved.