Selective estrogen-receptor modulators suppress microglial activation and neuronal cell death via an estrogen receptor-dependent pathway
Selective estrogen-receptor modulators suppress microglial activation and neuronal cell death via an estrogen receptor-dependent pathway
复制标题
DOI：
10.1016/j.jsbmb.2014.10.002
复制
发表时间：
2015-01-01
影响因子：
4.1
通讯作者：
Yamazaki, Takeshi
中科院分区：
文献类型：
--
作者：
Ishihara, Yasuhiro;Itoh, Kouichi;Yamazaki, Takeshi
越来越多的证据表明，类固醇激素，特别是17 -雌二醇（E2），通过减弱小胶质细胞的过度激活来保护神经细胞。然而，E2在临床上的使用存在争议，因为它在生殖器官中的外周作用以及它可能增加子宫内膜癌和乳腺癌的风险。选择性雌激素受体调节剂（SERMs）与雌激素受体（ER）结合，但其作为ER激动剂或拮抗剂的作用依赖于靶组织。由于SERMs在生殖器官中具有抗雌激素作用，因此其致癌风险很小，但其在大脑中的作用尚不清楚。在这项研究中，我们研究了SERMs他莫昔芬（Tam）和雷洛昔芬（Rix）对小胶质细胞激活和随后的神经元损伤的影响。Tam和Rix抑制了脂多糖（LPS）诱导的大鼠原代小胶质细胞中促炎细胞因子和趋化因子表达的增加。经Tam或Rlx预处理的小胶质条件培养基可显著减轻LPS单独处理的小胶质条件培养基引起的SH-SY5Y细胞损伤。大鼠原代小胶质细胞主要在细胞核中表达内质网α和内质网β，因此我们使用纯内质网拮抗剂ic1182,780研究了内质网参与Tam和Rix对小胶质细胞激活的抑制作用。ic1182,780预处理可消除SERMs对小胶质细胞活化的抑制作用，以及对SH-SY5Y细胞的保护作用。利用含有三种雌激素反应元件（EREs）的载体进行荧光素酶检测发现，Tam和Rlx激活了大鼠初级小胶质细胞中雌激素介导的转录。综上所述，这些结果表明Tam和Rix通过er介导的转录途径抑制小胶质细胞激活和随后的神经元细胞死亡。基于其抑制神经炎症的能力，serm可能代表了一种新的治疗中枢神经系统疾病的策略。(C) 2014 Elsevier Ltd.版权所有。
Growing evidence shows that steroid hormones, especially 17 beta-estradiol (E2), protect neuronal cells by attenuating excess activation of microglia. However, the use of E2 in the clinic is controversial because of its peripheral actions in reproductive organs and its potential to increase risk for endometrial cancer and breast cancer. Selective estrogen-receptor modulators (SERMs) bind to estrogen receptors (ERs), but their effects as ER agonists or antagonists are dependent on the target tissue. SERMs pose very little cancer risk as a result of their anti-estrogen action in reproductive organs, but their action in the brain is not well understood. In this study, we investigated the effects of SERMs tamoxifen (Tam) and raloxifene (Rix) on microglial activation and subsequent neuronal injury. Tam and Rix suppressed the increases in proinflammatory cytokines and chemokine expression that were induced by lipopolysaccharide (LPS) in rat primary microglia cultures. The microglial-conditioned media pretreated with Tam or Rlx significantly attenuated cellular injury in SH-SY5Y cells elicited by microglial-conditioned media treated with LPS alone. Rat primary microglia expressed ER alpha and ER beta primarily in the nucleus, and thus we examined the involvement of ERs in the suppressive action of Tam and Rix on microglial activation using a pure ER antagonist, IC1182,780. Pretreatment with IC1182,780 abolished the suppressive effects of SERMs on microglial activation, as well as their protective action on SH-SY5Y cells. A luciferase assay using a vector with three estrogen response elements (EREs) revealed that Tam and Rlx activated ERE-mediated transcription in rat primary microglia. Taken together, these results suggest that Tam and Rix suppress microglial activation and subsequent neuronal cell death via an ER-mediated transcription pathway. SERMs could represent a novel therapeutic strategy for disorders of the central nervous system based on their ability to suppress neuroinflammation. (C) 2014 Elsevier Ltd. All rights reserved.