Morissette M, Le Saux M, D'Astous M, Jourdain S, Al Sweidi S, Morin N, Estrada-Camarena E, Mendez Pablo, Garcia-Segura Luis Miguel, Di Paolo T
Molecular Endocrinology and Oncology Research Center, Medical Center and Faculty of Pharmacy, Laval University, 2705 Laurier Boulevard, Sainte-Foy, Québec, Canada.
J Steroid Biochem Mol Biol. 2008 Feb;108(3-5):327-38. doi: 10.1016/j.jsbmb.2007.09.011. Epub 2007 Sep 7.
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 ERalpha and ERbeta 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 ERalpha agonist, PPT, is shown as estradiol to modulate hippocampal NMDA receptors and AMPA receptors in cortex and striatum of ovariectomized rats whereas the ERbeta agonist DPN is inactive. Striatal DPN activity suggests implication of ERbeta in estradiol modulation of D2 receptors and transporters in ovariectomized rats and is supported by the lack of effect of estradiol in ERbeta knockout (ERKObeta) mice. Both ERalpha and ERbeta agonists modulate striatal preproenkephalin (PPE) gene expression in ovariectomized rats. In male mice PPT protects against MPTP toxicity to striatal dopamine; this implicates Akt/GSK3beta signaling and the apoptotic regulators Bcl2 and Bad. This suggests a role for ERalpha in striatal dopamine neuroprotection. ERKOalpha mice are more susceptible to MPTP toxicity and not protected by estradiol; differences in ERKObeta mice are subtler. These results suggest therapeutic potential for the brain of ER specific agonists.
临床和实验研究表明，雌激素在大脑中具有调节作用，并提示其在精神疾病和神经退行性疾病中具有有益作用。雌激素受体ERα和ERβ存在于大脑中，靶向这些受体可能带来选择性并降低患癌风险。本文综述了雌激素受体在雌二醇对多巴胺、阿片类和谷氨酸神经传递作用中的影响。结果显示，ERα激动剂PPT与雌二醇一样，可调节去卵巢大鼠海马中的NMDA受体以及皮质和纹状体中的AMPA受体，而ERβ激动剂DPN则无此活性。纹状体中DPN的活性表明ERβ参与了去卵巢大鼠中雌二醇对D2受体和转运体的调节，这一观点得到了雌二醇对ERβ基因敲除（ERKObeta）小鼠无作用的支持。ERα和ERβ激动剂均可调节去卵巢大鼠纹状体前脑啡肽原（PPE）基因的表达。在雄性小鼠中，PPT可保护纹状体多巴胺免受MPTP毒性影响；这涉及Akt/GSK3β信号通路以及凋亡调节因子Bcl2和Bad。这表明ERα在纹状体多巴胺神经保护中发挥作用。ERKOα小鼠对MPTP毒性更敏感，且不受雌二醇保护；ERKObeta小鼠的差异则较为细微。这些结果提示了ER特异性激动剂在脑部的治疗潜力。
