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Abstract 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 of 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 activation of MAPKs and STAT3. Incubation with the resulted astrocyte conditioned media caused no change in 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 NF-κB pathway, but has no impact on LPS-stimulated astrocyte activation. While the effect 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. Keywords: paroxetine, astrocytes, microglia, neuroinflammation, Parkinson’s disease
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