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Paroxetine ameliorates lipopolysaccharide-induced microglia activation via differential regulation of MAPK signaling.

Abstract：

BACKGROUND:Paroxetine, a selective serotonin reuptake inhibitor for counteracting depression, has been recently suggested as having a role in prevention of dopaminergic neuronal degeneration in substantia nigra, a hallmark of Parkinson's disease (PD). The pathogenesis of this type of neurological disorders often involves the activation of microglia and associated inflammatory processes. Thus in this study we aimed to understand the role of paroxetine in microglia activation and to elucidate the underlying mechanism(s). METHODS:BV2 and primary microglial cells were pretreated with paroxetine and stimulated with lipopolysaccharide (LPS). Cells were assessed for the responses of pro-inflammatory mediator and cytokines, and the related signaling pathways were evaluated and analyzed in BV2 cells. RESULTS:Paroxetine significantly inhibited LPS-induced production of nitric oxide (NO) and pro-inflammatory cytokines such as TNF-α and IL-1β. Further analysis showed inducible nitric oxide synthase (iNOS) and mRNA expression of TNF-α and IL-1β were attenuated by paroxetine pretreatment. Analyses in signaling pathways demonstrated that paroxetine led to suppression of LPS-induced JNK1/2 activation and baseline ERK1/2 activity, but had little effect on the activation of p38 and p65/NF-κB. Interference with specific inhibitors revealed that paroxetine-mediated suppression of NO production was via JNK1/2 pathway while the cytokine suppression was via both JNK1/2 and ERK1/2 pathways. Furthermore, conditioned media culture showed that paroxetine suppressed the microglia-mediated neurotoxicity. CONCLUSIONS:Paroxetine inhibits LPS-stimulated microglia activation through collective regulation of JNK1/2 and ERK1/2 signaling. Our results indicate a potential role of paroxetine in neuroprotection via its anti-neuroinflammatory effect besides targeting for depression.

journal_name

J Neuroinflammation

journal_title

Journal of neuroinflammation

authors

Liu RP,Zou M,Wang JY,Zhu JJ,Lai JM,Zhou LL,Chen SF,Zhang X,Zhu JH

doi

10.1186/1742-2094-11-47

subject

Has Abstract

pub_date

2014-03-12 00:00:00

pages

issn

1742-2094

pii

1742-2094-11-47

journal_volume

pub_type

杂志文章

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Paroxetine ameliorates lipopolysaccharide-induced microglia activation via differential regulation of MAPK signaling.