Article

Inhibitory effects of SSRIs on IFN-γ induced microglial activation through the regulation of intracellular calcium.

Department of Neuropsychiatry, Graduate School of Medicine, Kyushu University, Maidashi 3-1-1, Higashi-Ku, Fukuoka City, Fukuoka 812-8582, Japan.
Progress in Neuro-Psychopharmacology and Biological Psychiatry (Impact Factor: 4.03). 10/2010; 34(7):1306-16. DOI: 10.1016/j.pnpbp.2010.07.015
Source: PubMed

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.

1 Follower
 · 
146 Views
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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
  • Source
    • "Several antidepressants have been found to prevent the neurodegenerative activation of microglia induced by LPS and cytokines in vitro [46] [47] [48] [49] [50] [51] [52]. This effect has been seen with different classes of antidepressants, including selective serotonin reuptake inhibitors, selective norepinephrine reuptake inhibitors, tricyclic antidepressants, and even ketamine. "
    [Show abstract] [Hide abstract]
    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; 2013:608654. DOI:10.1155/2013/608654 · 2.93 Impact Factor
  • Source
    • "While, recent brain imaging and histological studies have indicated microglial activation in the brain of people with psychiatric disorders such as schizophrenia, depression, and autism (Radewicz et al., 2000; Steiner et al., 2008; Van Berckel et al., 2008; Doorduin et al., 2009; Morgan et al., 2010; Takano et al., 2010). Psychotropic drugs have long been regarded to have effects solely on neurons and neuronal networks including synapses, while our rodent in vitro studies have proved the novel effect of psychotropic drugs directly on microglia by suppressing release of inflammatory cytokines and free radicals (Kato et al., 2007, 2008, 2011a,b; Horikawa et al., 2010). Based on the abovementioned findings, we have proposed a microglial contribution to psychiatric disorders (Monji et al., 2009; Kato et al., 2011a). "
Show more