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.

The role of the kynurenine pathway in suicidality in adolescent major depressive disorder

“…This hypothesis is supported by the recent report of increased CSF QUIN, along with concomitant increases of interleukin (IL)-6 in suicidal individuals compared to healthy controls (Erhardt et al, 2013). In addition, the possible role of inflammatory processes in suicide in our sample can also be inferred by the enhanced significant findings of the KYN/TRP ratio and TRP subsequent to the exclusion of participants treated with psychotropic medications, known to have anti-inflammatory effects (Kostadinov et al, 2014; Liu et al, 2014; Obuchowicz et al, 2014). …”

“…Hypotheses were that depressed suicidal adolescents would exhibit increased KP activation, indexed by increased IDO (quantified by KYN/TRP), KYN and 3-HAA, and decreased TRP. Since psychotropic medications are known to have anti-inflammatory effects (Kostadinov et al, 2014; Liu et al, 2014; Obuchowicz et al, 2014), analyses were repeated while excluding medicated participants. Finally, we explored whether KP metabolites differed between subgroups of depressed adolescents who were actively suicidal and those with prior attempts, both of which were included in the suicidal group.…”

Retracted: Anti‐inflammatory properties of tianeptine on lipopolysaccharide‐induced changes in microglial cells involve toll‐like receptor‐related pathways

“…It should be admitted that this model has some limitations because LPS treatment does not totally reflect the neuroinflammation observed in pathological conditions such as depression, but according to the published data, this model may be useful for evaluating whether tianeptine exhibits anti-inflammatory activity in microglia cells (Liu et al 2011(Liu et al , 2014Obuchowicz et al 2014).…”

Transforming growth factor-β1 acts via TβR-I on microglia to protect against MPP+-induced dopaminergic neuronal loss

“…Neuroinflammation has been largely reported to be involved in PD pathogenesis (Chung et al, 2010;Liu et al, 2014;Nagatsu and Sawada, 2005;Ouchi et al, 2005). Excessive activation of microglia, the innate immune cells residing in the brain, is considered as a major factor in neuroinflammation (Amor et al, 2010;Liu et al, 2014;Russo et al, 2014).…”

“…Excessive activation of microglia, the innate immune cells residing in the brain, is considered as a major factor in neuroinflammation (Amor et al, 2010;Liu et al, 2014;Russo et al, 2014). Under physiological conditions, microglia exhibit a deactivated phenotype that is associated with production of anti-inflammatory and neurotrophic factors (Streit, 2002).…”