Quetiapine Inhibits Microglial Activation by Neutralizing Abnormal STIM1-Mediated Intercellular Calcium Homeostasis and Promotes Myelin Repair in a Cuprizone-Induced Mouse Model of Demyelination
Quetiapine Inhibits Microglial Activation by Neutralizing Abnormal STIM1-Mediated Intercellular Calcium Homeostasis and Promotes Myelin Repair in a Cuprizone-Induced Mouse Model of Demyelination
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喹硫平通过中和异常 STIM1 介导的细胞间钙稳态来抑制小胶质细胞活化并促进铜宗诱导的脱髓鞘小鼠模型中的髓磷脂修复
DOI：
10.3389/fncel.2015.00492
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发表时间：
2015-12
影响因子：
5.3
通讯作者：
Xiao Lan
中科院分区：
文献类型：
--
作者：
Wang Hanzhi;Liu Shubao;Tian Yanping;Wu Xiyan;He Yangtao;Li Chengren;Namaka Michael;Kong Jiming;Li Hongli;Xiao Lan
小胶质细胞激活被认为是神经炎症和精神疾病发病机制中的一个关键过程。几种抗精神病药物（APD）已被证明在体外显示对小胶质细胞活化的抑制作用，可能是通过抑制细胞内钙（Ca 2+）浓度升高。然而，确切的潜在机制仍然难以捉摸。在这项研究中，我们的目的是研究quetioline（Que），一种非典型的APD，对小胶质细胞激活的抑制作用。我们利用慢性cuprizone（CPZ）诱导的脱髓鞘小鼠模型来确定Que对小胶质细胞活化的直接影响。我们的研究结果表明，治疗Que显着减少募集和激活的小胶质细胞/巨噬细胞的胼胝体病变，促进髓鞘再生后CPZ撤出。我们的体外研究也证实了Que对脂多糖（LPS）诱导的小胶质细胞N9活化的直接作用，其中Que显著抑制一氧化氮（NO）和肿瘤坏死因子α（TNF-α）的释放。此外，我们证明了用Que预处理，中和了LPS诱导的STIM 1的上调，并降低了LPS和毒胡萝卜素（Tg）诱导的钙池操纵的Ca 2+内流（SOCE）。最后，我们发现Que预处理显著减少了LPS激活的原代小胶质细胞中核因子κ B（NF-κB）p65亚基从胞浆到胞核的移位。总体而言，我们的数据表明，Que可能通过中和LPS诱导的异常STIM 1介导的细胞间钙稳态来抑制小胶质细胞活化。
Microglial activation has been considered as a crucial process in the pathogenesis of neuroinflammation and psychiatric disorders. Several antipsychotic drugs (APDs) have been shown to display inhibitory effects on microglial activation in vitro, possibly through the suppression of elevated intracellular calcium (Ca2+) concentration. However, the exact underlying mechanisms still remain elusive. In this study, we aimed to investigate the inhibitory effects of quetiapine (Que), an atypical APD, on microglial activation. We utilized a chronic cuprizone (CPZ)-induced demyelination mouse model to determine the direct effect of Que on microglial activation. Our results showed that treatment with Que significantly reduced recruitment and activation of microglia/macrophage in the lesion of corpus callosum and promoted remyelination after CPZ withdrawal. Our in vitro studies also confirmed the direct effect of Que on lipopolysaccharide (LPS)-induced activation of microglial N9 cells, whereby Que significantly inhibited the release of nitric oxide (NO) and tumor necrosis factor α (TNF-α). Moreover, we demonstrated that pretreatment with Que, neutralized the up-regulation of STIM1 induced by LPS and declined both LPS and thapsigargin (Tg)-induced store-operated Ca2+ entry (SOCE). Finally, we found that pretreatment with Que significantly reduced the translocation of nuclear factor kappa B (NF-κB) p65 subunit from cytoplasm to nuclei in LPS-activated primary microglial cells. Overall, our data suggested that Que may inhibit microglial activation by neutralization of the LPS-induced abnormal STIM1-mediated intercellular calcium homeostasis.
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影响因子：
3.2
作者：
Riedel M;Müller N;Strassnig M;Spellmann I;Severus E;Möller HJ
通讯作者：
Möller HJ
喹硫平减轻 C57BL/6 小鼠大脑中铜宗诱导的白质病理
影响因子：
4.5
作者：
Li, Xin-Min;Jiang, Wengao;Li, Xiaokun;Xiao, Lan;Yan, Bin;Wang, Yanlin;Bi, Xiaoying;Kong, Jiming;Xu, Haiyun;Zhang, Yanbo;He, Jue
通讯作者：
He, Jue
影响因子：
8.7
作者：
通讯作者：
--
影响因子：
4.7
作者：
Kato, Takahiro;Mizoguchi, Yoshito;Kanba, Shigenobu
通讯作者：
Kanba, Shigenobu
影响因子：
4.5
作者：
C. Watkins;S. Andrews
通讯作者：
C. Watkins;S. Andrews