BACKGROUND Astrocytes are the most abundant glial cells in a brain that mediate inflammatory responses and provide trophic support for neurons. We have previously disclosed that paroxetine, a common selective serotonin reuptake inhibitor, ameliorates LPS-induced microglia activation. However, it remains elusive for the role of paroxetine in astrocytic responses. METHODS Isolated primary astrocytes were pretreated with paroxetine and stimulated with different stimuli, lipopolysaccharide (LPS) or microglia conditioned medium pre-activated with LPS (M/Lps). Inflammatory and neurotrophic responses, underlying mechanisms and the impact on neuronal survival were assessed. RESULTS Paroxetine had no impact on LPS-stimulated iNOS, TNF-α, and IL-1β expression, but inhibited M/Lps-induced TNF-α and IL-1β expression in primary astrocytes. Paroxetine suppressed M/Lps- but not LPS-induced activation of NF-κB and had no impact on the activation of MAPKs and STAT3. Incubation with the resulted astrocyte conditioned media caused no change in the viability of SH-SY5Y cells. BDNF and MANF mRNA expressions were upregulated by M/Lps and paroxetine, respectively. However, M/Lps- or LPS-induced extracellular releases of NO, TNF-α, and/or BDNF in astrocytes were in minor amount compared to those by microglia. CONCLUSIONS Paroxetine ameliorates the reactive microglia-mediated inflammatory responses in astrocytes partially via inhibition of the NF-κB pathway but has no impact on LPS-stimulated astrocyte activation. While the effects of paroxetine on secondary astrocytic responses are not robust compared to its effect on the innate immune responses of microglia, the results together may implicate a therapeutic potential of paroxetine against neuroinflammation-associated neurological disorders such as Parkinson's disease.

中文翻译：

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帕罗西汀抑制原代星形胶质细胞中的反应性小胶质细胞介导的但不是脂多糖诱导的炎症反应。

背景技术星形胶质细胞是大脑中最丰富的神经胶质细胞，其介导炎症反应并为神经元提供营养支持。我们先前曾披露过，帕罗西汀是一种常见的选择性5-羟色胺再摄取抑制剂，可改善LPS诱导的小胶质细胞活化。然而，对于帕罗西汀在星形细胞反应中的作用仍然难以捉摸。方法用帕罗西汀预处理分离的原代星形胶质细胞，并用经LPS（M / Lps）预激活的不同刺激，脂多糖（LPS）或小胶质细胞条件培养基刺激。评估了炎症和神经营养反应，潜在机制以及对神经元存活的影响。结果帕罗西汀对LPS刺激的iNOS，TNF-α和IL-1β表达无影响，但抑制了M / Lps诱导的原代星形胶质细胞中TNF-α和IL-1β的表达。帕罗西汀抑制M / Lps-但不抑制LPS诱导的NF-κB激活，并且对MAPKs和STAT3的激活没有影响。与产生的星形胶质细胞条件培养基一起孵育不会引起SH-SY5Y细胞活力的改变。BDNF和MANF mRNA表达分别由M / Lps和帕罗西汀上调。但是，与小胶质细胞相比，星形胶质细胞中由M / Lps或LPS诱导的NO，TNF-α和/或BDNF的细胞外释放较少。结论帕罗西汀通过抑制NF-κB途径部分改善了星形胶质细胞中反应性小胶质细胞介导的炎症反应，但对LPS刺激的星形胶质细胞活化没有影响。尽管帕罗西汀对继发性星形胶质细胞反应的影响与其对小胶质细胞先天免疫反应的影响相比并不牢固，