Selective estrogen receptor-beta (SERM-beta) compounds modulate raphe nuclei tryptophan hydroxylase-1 (TPH-1) mRNA expression and cause antidepressant-like effects in the forced swim test
Selective estrogen receptor-beta (SERM-beta) compounds modulate raphe nuclei tryptophan hydroxylase-1 (TPH-1) mRNA expression and cause antidepressant-like effects in the forced swim test
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DOI：
10.1016/j.neuropharm.2012.07.004
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发表时间：
2012-11-01
影响因子：
4.7
通讯作者：
Rohrer, S. P.
中科院分区：
文献类型：
--
作者：
Clark, J. A.;Alves, S.;Rohrer, S. P.
雌激素通过两种分子上不同的受体起作用，称为雌激素受体α（ER α）和雌激素受体β（ER β），它们以相似的亲和力结合雌二醇并介导雌激素在全身的作用。ER α在生殖生理和行为中起主要作用，并介导子宫、乳腺和骨骼等组织中的经典雌激素信号传导。然而，ER β调节卵巢、免疫系统、前列腺、胃肠道和下丘脑中的雌激素信号，并且有一些证据表明ER β可以调节ER α活性。此外，ER β敲除研究和CNS中的受体分布分析表明，该受体可能在情绪和认知的调节中发挥作用。近年来，几种ER β特异性化合物（选择性雌激素受体β调节剂; SERM-beta）已经变得可用，并且研究表明这些化合物在缓解更年期症状、预防乳腺癌、具有炎症成分的疾病、骨质疏松症、心血管疾病和炎性肠病以及调节情绪和焦虑中的潜在效用。在这里，我们证明了使用两种SERM-β化合物，SERM-β 1和SERM-β 2获得的抗抑郁样作用。这些化合物在基于细胞的雌激素反应元件（ERE）反式激活测定中显示出对ER β的完全激动剂活性。如使用基于MCF-7乳腺癌细胞的测定法所确定的，SERM-beta 1和2相对于乳腺是非增殖性的，并且如通过评估SERM-beta化合物对未成熟大鼠子宫重量和鼠子宫重量的影响所确定的，在子宫中是非增殖性的。体内SERM-β 1和2是脑渗透剂，并且在用于诱导色氨酸羟化酶mRNA和孕酮受体蛋白的鼠中缝背核测定中显示剂量依赖性功效。这些化合物在小鼠强迫游泳试验中显示出活性，并急性促进大鼠海马神经发生。总之，这些数据表明ER β可能在调节情绪中起重要作用，并且本文所述的ER β特异性化合物将是用于探测ER β激动剂用于治疗神经内分泌相关情绪障碍和绝经期症状的效用的有用工具。(C)2012爱思唯尔有限公司保留所有权利。
Estrogen acts through two molecularly distinct receptors termed estrogen receptor alpha (ER alpha) and estrogen receptor beta (ER beta) which bind estradiol with similar affinities and mediate the effects of estrogen throughout the body. ER alpha plays a major role in reproductive physiology and behavior, and mediates classic estrogen signaling in such tissues as the uterus, mammary gland, and skeleton. ER beta, however, modulates estrogen signaling in the ovary, the immune system, prostate, gastrointestinal tract, and hypothalamus, and there is some evidence that ER beta can regulate ER alpha activity. Moreover, ER beta knockout studies and receptor distribution analyses in the CNS suggest that this receptor may play a role in the modulation of mood and cognition. In recent years several ER beta-specific compounds (selective estrogen receptor beta modulators; SERM-beta) have become available, and research suggests potential utility of these compounds in menopausal symptom relief, breast cancer prevention, diseases that have an inflammatory component, osteoporosis, cardiovascular disease, and inflammatory bowel disease, as well as modulation of mood, and anxiety. Here we demonstrate an antidepressant-like effect obtained using two SERM-beta compounds, SERM-betal and SERM-beta2. These compounds exhibit full agonist activity at ER beta in a cell based estrogen response element (ERE) transactivation assay. SERM-betal and 2 are non-proliferative with respect to breast as determined using the MCF-7 breast cancer cell-based assay and non-proliferative in the uterus as determined by assessing the effects of SERM-beta compounds on immature rat uterine weight and murine uterine weight. In vivo SERM-betal and 2 are brain penetrant and display dose dependent efficacy in the murine dorsal raphe assays for induction of tryptophan hydroxylase mRNA and progesterone receptor protein. These compounds show activity in the murine forced swim test and promote hippocampal neurogenesis acutely in rats. Taken together these data suggest that ER beta may play an important role in modulating mood and the ER beta specific compounds described herein will be useful tools for probing the utility of an ER beta agonist for treating neuroendocrine-related mood disturbance and menopausal symptoms. (C) 2012 Elsevier Ltd. All rights reserved.