Fluoxetine prevents LPS-induced degeneration of nigral dopaminergic neurons by inhibiting microglia-mediated oxidative stress
Fluoxetine prevents LPS-induced degeneration of nigral dopaminergic neurons by inhibiting microglia-mediated oxidative stress
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DOI：
10.1016/j.brainres.2010.09.049
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发表时间：
2010-12-06
期刊：
影响因子：
2.9
通讯作者：
Jin, Byung K.
中科院分区：
文献类型：
--
作者：
Chung, Eun S.;Chung, Young C.;Jin, Byung K.
脂多糖（LPS）诱导的小胶质细胞活化导致黑质多巴胺（DA）能神经元变性。在此，我们检测了氟西汀是否在体内阻止LPS诱导的大鼠黑质（SN）DA变性。酪氨酸羟化酶（TH）免疫染色显示黑质DA能神经元明显丢失（通过OX 42和ED 1免疫组织化学显示），活性氧（ROS）的产生（通过氢乙啶组织化学评估），免疫组化双标记法显示，黑质DA能神经元的诱导型一氧化氮合酶（iNOS）表达增加在活化的小胶质细胞内，LPS还诱导NADPH氧化酶的胞质组分p67（Phox）易位到SN小胶质细胞的膜，表明NADPH氧化酶的活化。LPS诱导的黑质DA神经元的损失被氟西汀部分抑制，并且观察到的神经保护作用与氟西汀介导的小胶质细胞NADPH氧化酶活化和iNOS上调的抑制有关，这些结果表明氟西汀及其类似物可有益于治疗神经变性疾病，例如与小胶质细胞衍生的氧化损伤相关的PD（C）2010 Elsevier B V保留所有权利
Lipopolysaccharide (LPS) induced microglial activation causes degeneration of nigral dopaminergic (DA) neurons Here, we examined whether fluoxetine prevents LPS induced degeneration of DA in the rat substantia nigra (SN) in vivo Seven days after LPS injection into the SN, immunostaining for tyrosine hydroxylase (TH) revealed a significant loss of nigral DA neurons Parallel activation of microglia (visualized by OX 42 and ED1 immunohistochemistry), production of reactive oxygen species (ROS) (assessed by hydroethidine histochemistry), and degeneration of nigral DA neurons were also observed in the SN Western blot analyses and double label immunohistochemistry showed an increase in the expression of inducible nitric oxide synthase (iNOS) within activated microglia LPS also induced translocation of p67(Phox) the cytosolic component of NADPH oxidase, to the membrane of SN microglia, indicating activation of NADPH oxidase The LPS-induced loss of nigral DA neurons was partially inhibited by fluoxetine, and the observed neuroprotective effects were associated with fluoxetine mediated suppression of microglial NADPH oxidase activation and iNOS upregulation, and decreased ROS generation and oxidative stress These results suggest that fluoxetine and analogs thereof may be beneficial for the treatment of neurodegenerative diseases such as PD that are associated with microglia derived oxidative damage (C) 2010 Elsevier B V All rights reserved