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Antidepressants inhibit interferon-γ-induced microglial production of IL-6 and nitric oxide
Abstract
Circumstantial evidence has suggested that activated microglia may be associated with the pathogenesis of depression. Pro-inflammatory cytokines may also be involved. Therefore, we examined the effects of various types of antidepressants, as well as the mood-stabilizer lithium chloride, on interferon-gamma (IFN-gamma)-induced microglial production of the pro-inflammatory mediators interleukin-6 (IL-6) and nitric oxide (NO). Treatment of the murine microglial 6-3 cells with 100 U/ml of IFN-gamma resulted in an eightfold increase in IL-6 and a tenfold increase in NO into the culture medium. Pretreatment with the selective serotonin reuptake inhibitor fluvoxamine, the relatively selective noradrenaline reuptake inhibitor reboxetine, or the non-selective monoaminergic reuptake inhibitor imipramine, significantly inhibited IL-6 and NO production in a dose-dependent manner. These inhibitions were reversed significantly by SQ 22536, a cyclic adenosine monophosphate (cAMP) inhibitor, and, except for reboxetine, by the protein kinase A (PKA) inhibitor Rp-adenosine3',5'-cyclic monophosphorothioate triethylammonium salt (Rp-3',5'-cAMPS). Lithium chloride, which is believed to act by inhibiting the calcium-dependent release of noradrenaline, had a different spectrum of action on microglial 6-3 cells. It enhanced IFN-gamma-stimulated IL-6 production and inhibited NO production. The inhibitory effect of lithium chloride was not reversed by either SQ 22536 or Rp-3',5'-cAMPS. These results suggest that antidepressants have inhibitory effects on IFN-gamma-activated microglia and these effects are, at least partially, mediated by the cAMP-dependent PKA pathway. On the other hand, the mood stabilizer and anti-manic agent lithium chloride has mixed effects on IFN-gamma-induced microglial activation.
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“pretreatment with imipramine, fluvoxamine, or reboxetine inhibited NO production in a dose-dependent manner in an activated microglia cell culture protocol [11].”
From Preclinical and Clinical Evidence of Antioxidant Effects of Antidepressant Agents: Implications for the Pathophysiology of Major Depressive Disorder (2012) · cites this paper as [11]
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Metadata
- Authors
- Hashioka, S., Klegeris, A., Monji, A., Kato, T., Sawada, M., McGeer, P. L., & Kanba, S.
- Affiliations
- Kyushu University (JP)
- University of British Columbia (CA)
- Research Institute of Environmental Medicine, Nagoya University (JP)
- Corresponding author
- Hashioka, Sadayuki
- Monji, Akira
- Venue
- Experimental Neurology
- Publisher
- Elsevier BV
- Published
- 2007-07
- Volume
- 206
- Issue
- 1
- Pages
- 33-42
- ISSN
- 0014-4886 (ISSN-L)
- OpenAlex
- W1970022478
- Cited by
- 198
- References
- 42
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 7 · 2023: 4 · 2022: 9 · 2021: 11 · 2020: 10 · 2019: 10 · 2018: 5 · 2017: 7 · 2016: 18 · 2015: 16 · 2014: 18 · 2013: 14 · 2012: 18
- FWCI
- 3.53
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Experimental Neurology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Keywords
- antidepressants, microglia, interferon-gamma, interleukin-6, nitric oxide, fluvoxamine, reboxetine, imipramine, lithium chloride, cAMP signaling, protein kinase A, microglial activation, depression, inflammatory cytokines, mood stabilizers
- MeSH terms
- Cyclic AMP, Animals, Antidepressive Agents, Antiviral Agents, Brain, Cell Line, Depressive Disorder, Dose-Response Relationship, Drug, Enzyme Inhibitors, Interferon-gamma, Mice, Inbred C57BL, Nitric Oxide, Neurotransmitter Uptake Inhibitors, Interleukin-6, Up-Regulation, Microglia, Cyclic AMP-Dependent Protein Kinases, Lithium Chloride, Antimanic Agents, MAP Kinase Signaling System, Mice, Cyclic AMP-Dependent Protein Kinase Type II
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