Differential and paradoxical roles of new-generation antidepressants in primary astrocytic inflammation.
Differential and paradoxical roles of new-generation antidepressants in primary astrocytic inflammation.
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新一代抗抑郁药在原发性星形细胞炎症中的差异和矛盾作用。
DOI：
10.1186/s12974-021-02097-z
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发表时间：
2021-02-18
影响因子：
9.3
通讯作者：
Zhu JH
中科院分区：
文献类型：
--
作者：
He JH;Liu RP;Peng YM;Guo Q;Zhu LB;Lian YZ;Hu BL;Fan HH;Zhang X;Zhu JH
选择性5 -羟色胺再摄取抑制剂（SSRIs）和5 -羟色胺-去甲肾上腺素再摄取抑制剂（SNRIs）是常用的新一代抑郁症药物。抑郁症状被认为与神经炎症密切相关。在这项研究中，我们使用了最新的培养和刺激方案，旨在了解星形胶质细胞对抗抑郁药的反应。采用神经基础无血清培养基分离培养原代星形胶质细胞。细胞用由补体成分1q、肿瘤坏死因子α和白细胞介素1α组成的细胞因子混合物处理，有或没有抗抑郁药预处理。分析了细胞活力、表型、炎症反应和潜在机制。所有SSRIs，包括帕罗西汀、氟西汀、舍曲林、西酞普兰和氟伏沙明，在应用剂量范围内显示出明显的细胞毒性，并对星形胶质细胞炎症反应产生悖论效应，表现为促进诱导型一氧化氮合酶（iNOS）和/或一氧化氮（NO），抑制白细胞介素6 （IL-6）和/或白细胞介素1β (IL-1β)。SNRI文拉法辛对星形胶质细胞的毒性最小，可抑制IL-6和IL-1β的产生，但对iNOS和no无影响。所有药物对星形细胞A1和A2型的极化均无调节作用。抗抑郁药通过抑制JNK1激活和STAT3基础活性在星形细胞炎症途径中的相关机制。该研究表明，抗抑郁药对星形胶质细胞具有不同的细胞毒性，并且对星形胶质细胞炎症具有不同的功能，这与SSRIs也自相矛盾。我们的研究结果为理解抗抑郁药治疗星形胶质细胞患者的不同疗效和耐受性提供了新的线索。在线版本包含补充材料，可在10.1186/s12974-021-02097-z获得。
Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are commonly used new-generation drugs for depression. Depressive symptoms are thought to be closely related to neuroinflammation. In this study, we used up-to-date protocols of culture and stimulation and aimed to understand how astrocytes respond to the antidepressants. Primary astrocytes were isolated and cultured using neurobasal-based serum-free medium. The cells were treated with a cytokine mixture comprising complement component 1q, tumor necrosis factor α, and interleukin 1α with or without pretreatments of antidepressants. Cell viability, phenotypes, inflammatory responses, and the underlying mechanisms were analyzed. All the SSRIs, including paroxetine, fluoxetine, sertraline, citalopram, and fluvoxamine, show a visible cytotoxicity within the range of applied doses, and a paradoxical effect on astrocytic inflammatory responses as manifested by the promotion of inducible nitric oxide synthase (iNOS) and/or nitric oxide (NO) and the inhibition of interleukin 6 (IL-6) and/or interleukin 1β (IL-1β). The SNRI venlafaxine was the least toxic to astrocytes and inhibited the production of IL-6 and IL-1β but with no impact on iNOS and NO. All the drugs had no regulation on the polarization of astrocytic A1 and A2 types. Mechanisms associated with the antidepressants in astrocytic inflammation route via inhibition of JNK1 activation and STAT3 basal activity. The study demonstrated that the antidepressants possess differential cytotoxicity to astrocytes and function differently, also paradoxically for the SSRIs, to astrocytic inflammation. Our results provide novel pieces into understanding the differential efficacy and tolerability of the antidepressants in treating patients in the context of astrocytes. The online version contains supplementary material available at 10.1186/s12974-021-02097-z.
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影响因子：
6.7
作者：
Filous AR;Silver J
通讯作者：
Silver J
DOI：
10.1083/jcb.85.3.890
发表时间：
1980-06
期刊：
The Journal of cell biology
影响因子：
--
作者：
McCarthy KD;de Vellis J
通讯作者：
de Vellis J
影响因子：
17.7
作者：
Bartels, Claudia;Wagner, Michael;Schneider, Anja
通讯作者：
Schneider, Anja
影响因子：
168.9
作者：
Cipriani, Andrea;Zhou, Xinyu;Xie, Peng
通讯作者：
Xie, Peng
影响因子：
5.6
作者：
Carvalho, L. A.;Garner, B. A.;Dew, T.;Fazakerley, H.;Pariante, C. M.
通讯作者：
Pariante, C. M.