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Published on: August 15, 2012
Paroxetine suppresses reactive microglia-mediated but not lipopolysaccharide-induced inflammatory responses in
Xiong Zhang1,2, Lan-Bing Zhu1, Jia-Hui He1
1Department of Geriatrics and Neurology, the Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325027, China.
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.
Insights
Paroxetine partially inhibits inflammation in astrocytes triggered by activated microglia, suggesting potential for neuroinflammation treatment. It does not affect direct LPS-induced astrocyte activation.
Area of Science:
- Neuroscience
- Neuroimmunology
- Pharmacology
Background:
- Astrocytes are key glial cells involved in brain inflammation and neuronal support.
- Paroxetine, a selective serotonin reuptake inhibitor, is known to reduce microglia activation.
- The specific effects of paroxetine on astrocyte responses remained unclear.
Purpose of the Study:
- To investigate the role of paroxetine in modulating astrocyte inflammatory and neurotrophic responses.
- To determine the impact of paroxetine on astrocyte activation pathways and neuronal survival.
Main Methods:
- Primary astrocytes were pretreated with paroxetine and stimulated with lipopolysaccharide (LPS) or LPS-activated microglia conditioned medium (M/Lps).
- Assessed inflammatory markers (iNOS, TNF-α, IL-1β), signaling pathways (NF-κB, MAPKs, STAT3), and neurotrophic factors (BDNF, MANF).
- Evaluated the effect of conditioned media on neuronal viability (SH-SY5Y cells).
Main Results:
- Paroxetine inhibited M/Lps-induced TNF-α and IL-1β expression but not LPS-induced expression.
- Paroxetine suppressed NF-κB activation in response to M/Lps but not LPS.
- Neurotrophic factor mRNA (BDNF, MANF) expressions were modulated; however, astrocyte-released inflammatory mediators were minimal compared to microglia.
Conclusions:
- Paroxetine ameliorates reactive microglia-mediated inflammation in astrocytes, partly via NF-κB inhibition.
- Paroxetine does not impact direct LPS-stimulated astrocyte activation.
- Results suggest a potential therapeutic role for paroxetine in neuroinflammation-associated disorders like Parkinson's disease.
