Inhibitory effects of SSRIs on IFN-γ induced microglial activation through the regulation of intracellular calcium
ABSTRACT Microglia, which are a major glial component of the central nervous system (CNS), have recently been suggested to mediate neuroinflammation through the release of pro-inflammatory cytokines and nitric oxide (NO). Microglia are also known to play a critical role as resident immunocompetent and phagocytic cells in the CNS. Immunological dysfunction has recently been demonstrated to be associated with the pathophysiology of depression. However, to date there have only been a few studies on the relationship between microglia and depression. We therefore investigated if antidepressants can inhibit microglial activation in vitro. Our results showed that the selective serotonin reuptake inhibitors (SSRIs) paroxetine and sertraline significantly inhibited the generation of NO and tumor necrosis factor (TNF)-α from interferon (IFN)-γ-activated 6-3 microglia. We further investigated the intracellular signaling mechanism underlying NO and TNF-α release from IFN-γ-activated 6-3 microglia. Our results suggest that paroxetine and sertraline may inhibit microglial activation through inhibition of IFN-γ-induced elevation of intracellular Ca(2+). Our results suggest that the inhibitory effect of paroxetine and sertraline on microglial activation may not be a prerequisite for antidepressant function, but an additional beneficial effect.
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- "The concentrations of antidepressant drugs used in this study were based on our previous study, which showed that these concentrations enhance expression of BDNF, PSD-95 and synaptophysin, as well as dendritic outgrowth in rat hippocampal neurons (Seo et al., 2014). Additionally, several studies reported a similar narrow concentration range for antidepressant effects on neurons (Wu et al., 1996; Post et al., 2000; Peng et al., 2008; Horikawa et al., 2010; Dikmen et al., 2011). The concentrations of ketamine were based on the observation that lower concentrations (<50 μM) had no effect on the phosphorylation of mTOR-mediated proteins, and higher concentrations (>500 μM) tended to reduce cell viability (data not shown). "
ABSTRACT: Recent studies suggest that ketamine produces antidepressant actions via stimulation of mammalian target of rapamycin (mTOR), leading to increased levels of synaptic proteins in the prefrontal cortex. Thus, mTOR activation may be related to antidepressant action. However, the mTOR signalling underlying antidepressant drug action has not been well investigated. The aim of the present study was to determine whether alterations in mTOR signalling were observed following treatment with antidepressant drugs, using ketamine as a positive control. Using Western blotting, we measured changes in the mTOR-mediated proteins and synaptic proteins in rat hippocampal cultures. Dendritic outgrowth was determined by neurite assay. Our findings demonstrated that escitalopram, paroxetine and tranylcypromine significantly increased levels of phospho-mTOR and its down-stream regulators (phospho-4E-BP-1 and phospho-p70S6K); fluoxetine, sertraline and imipramine had no effect. All drugs tested increased up-stream regulators (phospho-Akt and phospho-ERK) levels. Increased phospho-mTOR induced by escitalopram, paroxetine or tranylcypromine was significantly blocked in the presence of specific PI3K, MEK or mTOR inhibitors, respectively. All drugs tested also increased hippocampal dendritic outgrowth and synaptic proteins levels. The mTOR inhibitor, rapamycin, significantly blocked these effects on escitalopram, paroxetine and tranylcypromine whereas fluoxetine, sertraline and imipramine effects were not affected. The effects of escitalopram, paroxetine and tranylcypromine paralleled those of ketamine. This study presents novel in vitro evidence indicating that some antidepressant drugs promote dendritic outgrowth and increase synaptic protein levels through mTOR signalling; however, other antidepressant drugs seem to act via a different pathway. mTOR signalling may be a promising target for the development of new antidepressant drugs.The International Journal of Neuropsychopharmacology 06/2014; 17(11):1-16. DOI:10.1017/S1461145714000534 · 4.01 Impact Factor
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- "Recent studies have shown that selective-serotonin-reuptake inhibitor medications can suppress immune cell activation and release of inflammatory cytokines in the periphery and ex-vivo (Diamond et al., 2006; Taler et al., 2007; Branco-de-Almeida et al., 2011). Notably, this immune-regulatory effect is not restricted only to the periphery, but can also affect microglia, the immune cells of the CNS (Hashioka et al., 2007; Horikawa et al., 2010). A recent meta-analysis of human depression studies showed that antidepressant treatment at least partially ameliorates the elevations of pro-inflammatory cytokines associated with the disorder (Hannestad et al., 2011). "
ABSTRACT: It has long been established in traditional forms of medicine and in anecdotal knowledge that the health of the body and the mind are inextricably linked. Strong and continually developing evidence now suggests a link between disorders which involve Hypothalamic-Pituitary-Adrenal axis (HPA) dysregulation and the risk of developing psychiatric disease. For instance, adverse or excessive responses to stressful experiences are built into the diagnostic criteria for several psychiatric disorders, including depression and anxiety disorders. Interestingly, peripheral disorders such as metabolic disorders and cardiovascular diseases are also associated with HPA changes. Furthermore, many other systemic disorders associated with a higher incidence of psychiatric disease involve a significant inflammatory component. In fact, inflammatory and endocrine pathways seem to interact in both the periphery and the central nervous system (CNS) to potentiate states of psychiatric dysfunction. This review synthesizes clinical and animal data looking at interactions between peripheral and central factors, developing an understanding at the molecular and cellular level of how processes in the entire body can impact on mental state and psychiatric health.Frontiers in Pharmacology 12/2013; 4:158. DOI:10.3389/fphar.2013.00158 · 3.80 Impact Factor
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- "Several antidepressants have been found to prevent the neurodegenerative activation of microglia induced by LPS and cytokines in vitro       . This effect has been seen with different classes of antidepressants, including selective serotonin reuptake inhibitors, selective norepinephrine reuptake inhibitors, tricyclic antidepressants, and even ketamine. "
ABSTRACT: Microglia, the brain's resident immune cells, are phagocytes of the macrophage lineage that have a key role in responding to inflammation and immune challenge in the brain. More recently, they have been shown to have a number of important roles beyond immune surveillance and response, including synaptic pruning during development and the support of adult neurogenesis. Microglial abnormalities have been found in several neuropsychiatric conditions, though in most cases it remains unclear whether these are causative or are a reaction to some other underlying pathophysiology. Here we summarize postmortem, animal, neuroimaging, and other evidence for microglial pathology in major depression, schizophrenia, autism, obsessive-compulsive disorder, and Tourette syndrome. We identify gaps in the existing literature and important areas for future research. If microglial pathology proves to be an important causative factor in these or other neuropsychiatric diseases, modulators of microglial function may represent a novel therapeutic strategy.Clinical and Developmental Immunology 04/2013; 2013(6048):608654. DOI:10.1155/2013/608654 · 2.93 Impact Factor