Progress in Neuro-Psychopharmacology and Biological Psychiatry
Inhibitory effects of SSRIs on IFN-γ induced microglial activation through the regulation of intracellular calcium
Research Highlights
►This study has examined the effects of antidepressants on interferon-γ-induced microglial activation in vitro. We have shown that paroxetine and sertraline have anti-inflammatory effects via the inhibition of microglial activation. Furthermore, this is the first report of the existence of serotonin transporters in microglial cells. Interestingly, our data suggest that the inhibitory effects of paroxetine and sertraline on microglial activation may not be mediated by serotonin transporters. Our results might shed some new light on the therapeutic strategies for the treatment of depression with anti-inflammatory/immunosuppressive agents.
Introduction
Accumulating data suggest the importance of immunological dysfunction in the pathophysiology of depression (Anisman, 2009, Miller et al., 2009, Muller and Schwarz, 2007, Raison et al., 2006, Schiepers et al., 2005, Dowlati et al., 2009). Microglia are generally considered to be the immune cells of the CNS and they respond to any kind of pathology with a reaction termed microglial activation (Hanisch and Kettenmann, 2007). Microglial activation plays an important role in the pathophysiology of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD) via the release of pro-inflammatory cytokines, nitric oxide (NO) or reactive oxygen species (Inoue and Tsuda, 2009, McGeer et al., 1993, Stoll and Jander, 1999). Furthermore, an elevated microglial density has been observed in patients with depression or schizophrenia who have committed suicide (Steiner et al., 2008).
It has been suggested that impaired hippocampal neurogenesis contributes to the pathogenesis of depression and it has been demonstrated that the neuroinflammation associated with microglial activation inhibits hippocampal neurogenesis (Duman, 2004, Ekdahl et al., 2003, Monje et al., 2003). These studies have further shown that indomethacin, a conventional non-steroidal anti-inflammatory drug, and minocycline, which inhibit microglial activation, can restore this impaired neurogenesis (Ekdahl et al., 2003, Monje et al., 2003). Pro-inflammatory cytokines such as interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) have been reported to be negative regulators of hippocampal neurogenesis (Monje et al., 2003, Vallieres et al., 2002, Iosif et al., 2006, Kaneko et al., 2006, Koo and Duman, 2008). It has also been reported that NO inhibits neurogenesis while nitric oxide synthase (NOS) inhibitors show antidepressant-like activity (Zhou et al., 2007, Joca and Guimaraes, 2006). Antidepressant treatment increases neurogenesis in adult hippocampus (Duman, 2004, Malberg et al., 2000, Santarelli et al., 2003) and the behavioral effects of antidepressants may, in part, be due to stimulation of such hippocampal neurogenesis (Santarelli et al., 2003).
In animal experiments, chronic administration of pro-inflammatory cytokines has been shown to induce symptoms similar to depression. These symptoms are referred to as sickness behavior and include loss of appetite, insomnia and lack of interest (Dantzer et al., 2008). Pro-inflammatory cytokines such as TNF-α and interferon (IFN)-γ activate the tryptophan- and serotonin-degrading enzyme indoleamine 2, 3-dioxygenase (IDO). The increased consumption of serotonin and its precursor tryptophan by activated IDO leads to a reduced availability of serotonin for serotonergic transmission (Muller and Schwarz, 2007). Furthermore, pro-inflammatory cytokines such as IL-1β and TNF-α also reduce serotonergic transmission through the activation of serotonin transporters (5-HTT) (Zhu et al., 2006).
The above data encourage speculation that antidepressants play an important role in the pathophysiology of depression through inhibitory effects on microglial activation. To our knowledge, only a few recent studies have shown that some antidepressants inhibited the production of NO and/or pro-inflammatory cytokines from activated microglia in vitro (Hashioka et al., 2007, Hwang et al., 2008, Lim et al., 2009, Obuchowicz et al., 2006, Vollmar et al., 2008).
In the present study, we demonstrate that antidepressants such as paroxetine and sertraline, that are typical selective serotonin reuptake inhibitors (SSRIs), also have an inhibitory effect on the release of NO and TNF-α from IFN-γ-induced microglial cells.
Some SSRIs have been reported to induce apoptosis through an effect on intracellular Ca2+ regulation in Burkitt lymphoma and human osteosarcoma cells (Serafeim et al., 2003, Chou et al., 2007). We have also recently reported that aripiprazole, which is used to treat depression, inhibited microglial activation through suppression of IFN-γ-induced elevation of intracellular Ca2+ in microglia (Kato et al., 2008). Therefore, we also investigated the effect of paroxetine and sertraline on intracellular Ca2+ regulation of microglia. We also investigated whether bupropion, and agomelatine that have much lower effect on 5-HTT than paroxetine and sertraline, have similar effects on microglia. Although antidepressant effect of agomelatine is debatable, agomelatine is reported to be an antidepressant at doses of 25–50 mg/day (Dubovsky and Warren 2009).
Section snippets
Materials
All experimental procedures were conducted in accordance with the Standard Guidelines for Animal Experiments of the Graduate School of Medicine, Kyushu University.
Sertraline was kindly gifted by Pfizer Inc. (New York, NY, USA). Paroxetine was purchased from Toronto Research Chemicals Inc. (North York, Canada). The JAK inhibitor 1 was purchased from Calbiochem (San Diego, CA, USA). Agomelatine, bupropion, serotonin, and all other main chemicals were purchased from Sigma (St. Louis, MO, USA).
The effect of paroxetine and sertraline on NO, TNF-α and IL-4 release by IFN-γ-activated microglia
To determine the effect of antidepressants on IFN-γ-induced NO release in microglial cells, the 6-3 microglial cells were pre-treated with DMSO (0.025%), paroxetine (0.5 or 5 μM), sertraline (0.5 or 5 μM), agomelatine (1 or 10 μM), or bupropion (1 or 10 μM) for 24 h, followed by treatment with IFN-γ (50 U/mL), in the continued presence of each drug, for 24 h. NO release was then assayed by measurement of the accumulation of NO2. Both paroxetine and sertraline significantly inhibited NO release in a
Discussion
In the present study, paroxetine and sertraline significantly inhibited the generation of NO and TNF-α from IFN-γ-activated microglia as well as to suppress the IFN-γ-induced elevation of [Ca2+]i in microglia. Neither paroxetine nor sertraline were toxic to microglial cells at their effective concentrations. In addition, these antidepressants significantly inhibited NO release from rat primary microglia activated by LPS (1 μg/mL), while they had no effect on the NO release from those activated
Conclusion
Inhibitory effects of paroxetine and sertraline on microglial activation reported in this paper shed some new light on the design of therapeutic strategies for the treatment of depression. Future study should focus on a detailed clarification of the molecular mechanism(s) by which antidepressants inhibit microglial activation and on confirmation of the results reported herein in in vivo studies.
Conflict of interest
The authors have no conflict of interest.
Acknowledgments
The present study was supported partly by a grant-in-aid from the Japan Society for the Promotion in Science. The authors thank Prof. Makoto Sawada of Nagoya University for providing us with the microglial cell line 6-3.
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2018, Journal of Affective DisordersCitation Excerpt :Thus, higher IL34/CD81 levels in patients with MDD in the present study have suggested neuronal damage and microglial dysfunction linked to the pathophysiology of MDD at least during the acute phase. Microglia are now highlighted for their involvement in the pathophysiology of various psychiatric disorders including delirium, Alzheimer's disease, schizophrenia, bipolar disorders, autism, and MDD (Haraguchi et al., 2017; Hayakawa et al., 2014; Horikawa et al., 2010; Kato et al., 2011a, 2013; Kuwano et al., 2018; Mizoguchi and Monji, 2017; Monji et al., 2009; Ohgidani et al., 2016; Sato-Kasai et al., 2016; Setiawan et al., 2018, 2015; Setoyama et al., 2016; Yirmiya et al., 2015). IL34/CD81 may be a useful biomarker to detect patients with various psychiatric disorders including MDD.