Paroxetine suppresses reactive microglia-mediated but not lipopolysaccharide-induced inflammatory responses in primary astrocytes
Paroxetine suppresses reactive microglia-mediated but not lipopolysaccharide-induced inflammatory responses in primary astrocytes
复制标题
帕罗西汀抑制原代星形胶质细胞中反应性小胶质细胞介导的炎症反应，但不抑制脂多糖诱导的炎症反应
DOI：
10.1186/s12974-020-1712-0
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发表时间：
2020-02-05
影响因子：
9.3
通讯作者：
Zhu, Jian-Hong
中科院分区：
文献类型：
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作者：
Zhang, Xiong;Zhu, Lan-Bing;Zhu, Jian-Hong
星形胶质细胞是大脑中最丰富的胶质细胞，介导炎症反应并为神经元提供营养支持。我们之前已经披露帕罗西汀，一种常见的选择性5 -羟色胺再摄取抑制剂，改善lps诱导的小胶质细胞活化。然而，帕罗西汀在星形细胞反应中的作用仍然难以捉摸。方法分离的原代星形胶质细胞经帕罗西汀预处理后，分别用脂多糖（LPS）或脂多糖（M/ LPS）预处理的小胶质细胞条件培养基刺激。评估炎症和神经营养反应、潜在机制和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M/ lps诱导的原代星形胶质细胞TNF-α和IL-1β表达。帕罗西汀抑制M/Lps诱导的NF-κ b活化，但不抑制Lps诱导的NF-κ b活化，对MAPKs和STAT3的活化没有影响。星形胶质细胞条件培养基对SH-SY5Y细胞的活性无影响。M/Lps和帕罗西汀分别上调BDNF和MANF mRNA的表达。然而，与小胶质细胞相比，M/Lps或Lps诱导的星形胶质细胞中NO、TNF-α和/或BDNF的细胞外释放量较少。结论帕罗西汀部分通过抑制NF-κB通路改善星形胶质细胞反应性炎症反应，但对lps刺激的星形胶质细胞活化无影响。虽然帕罗西汀对继发性星形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强大，但这些结果可能暗示帕罗西汀对神经炎症相关神经系统疾病（如帕金森病）的治疗潜力。
BackgroundAstrocytes 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.MethodsIsolated 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.ResultsParoxetine 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.ConclusionsParoxetine 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.