Inhibition of glial inflammatory activation and neurotoxicity by tricyclic antidepressants
Inhibition of glial inflammatory activation and neurotoxicity by tricyclic antidepressants
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DOI：
10.1016/j.neuropharm.2008.06.045
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发表时间：
2008-10-01
影响因子：
4.7
通讯作者：
Suk, Kyoungho
中科院分区：
文献类型：
--
作者：
Hwang, Jaegyu;Zheng, Long Tai;Suk, Kyoungho
神经胶质细胞激活和神经炎症过程在阿尔茨海默病、帕金森病和HIV痴呆等神经退行性疾病的发病机制中发挥着重要作用。激活的神经胶质细胞可以分泌多种促炎细胞因子和神经毒性介质，可能与神经细胞死亡有关。在这些情况下，抑制胶质细胞的激活可能会减轻神经退行性变。本研究以培养的脑细胞为模型，研究了三环类抗抑郁药的抗炎和神经保护作用。结果表明，氯丙咪嗪和丙咪嗪显著减少小胶质细胞和星形胶质细胞培养中一氧化氮或肿瘤坏死因子-α的产生。氯丙咪嗪和丙咪嗪也在mRNA水平上减弱诱导型一氧化氮合酶和促炎细胞因子如白介素1β和肿瘤坏死因子的表达。此外，氯丙咪嗪和丙咪嗪还可抑制脂多糖刺激的小胶质细胞中I kappaB的降解、核转录因子kappaB p65亚基的核转位和p38丝裂原活化蛋白激酶的磷酸化。此外，在小胶质细胞/神经元共培养中，氯丙咪嗪和丙咪嗪具有神经保护作用，因为这两种药物减少了小胶质细胞介导的神经母细胞瘤细胞死亡。因此，这些结果提示氯丙咪嗪和丙咪嗪通过调节神经胶质细胞的激活在中枢神经系统具有抗炎和神经保护作用。(C)2008爱思唯尔有限公司。保留所有权利。
Glial activation and neuroinflammatory processes play an important role in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and HIV dementia. Activated glial cells can secrete various proinflammatory cytokines and neurotoxic mediators, which may contribute to neuronal cell death. Inhibition of glial activation may alleviate neurodegeneration under these conditions. In the present study, the antiinflammatory and neuroprotective effects of tricyclic antidepressants were investigated using cultured brain cells as a model. The results showed that clomipramine and imipramine significantly decreased the production of nitric oxide or tumor necrosis factor-alpha (TNF-alpha) in microglia and astrocyte cultures. Clomipramine and imipramine also attenuated the expression of inducible nitric oxide synthase and proinflammatory cytokines such as interleukin-1 beta and TNF-a at mRNA levels. In addition, clomipramine and imipramine inhibited I kappa B degradation, nuclear translocation of the p65 subunit of NF-kappa B, and phosphorylation of p38 mitogen-activated protein kinase in the lipopolysaccharide-stimulated microglia cells. Moreover, clomipramine and imipramine were neuroprotective as the drugs reduced microglia-mediated neuroblastoma cell death in a microglia/neuron co-culture. Therefore, these results imply that clomipramine and imipramine have anti inflammatory and neuroprotective effects in the central nervous system by modulating glial activation. (c) 2008 Elsevier Ltd. All rights reserved.