Imipramine enhances the expression of astrocytic interleukin-10 under inflammatory state

[Speaker] Yosuke Yamawaki:1
[Co-author] Satomi Shirawachi:1, Munechika Takaishi:1, Shigeto Yamawaki:2, Takashi Kanematsu:1
1:Department of Cellular and Molecular Pharmacology Institute of Biomedical and Health Sciences, Hiroshima University, Japan, 2:Department of Psychiatry and Neurosciences, Institute of Biomedical and Health Sciences, Hiroshima University, Japan

Many studies revealed compelling evidence that inflammation is involved in major depressive disorder (MDD). Peripheral injection of lipopolysaccharide (LPS) induced neuro-inflammation with the elevation of pro-inflammatory cytokines and caused depressive behavior in a rodent. Although antidepressants ameliorate a LPS-induced depressive state in animal models, pharmacological mechanism remains unclear. Glial cells are the target of an antidepressant and play a key role in regulating neuro-inflammation progress. Therefore, we hypothesized that an anti-inflammatory effect of antidepressants in glial cells is important for anti-depressant properties. Here, we investigated the mechanism of anti-inflammatory effect of an antidepressant.
[Materials and Methods]
LPS (0.5 mg/kg) or imipramine (30 mg/kg) were injected intraperitoneally into mice. For evaluating depressive state and locomotor activity, tail suspension test (TST) and open-field locomotor test were performed, respectively. Primary astrocytes prepared from neonatal mice were treated with LPS (10 ng/mL) and/or imipramine (50 μM). The expression of protein and mRNA were analyzed by western blot and quantitative PCR analyses, respectively.
LPS administration increased pro-inflammatory cytokines such as interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α; in the hippocampus and immobility time in TST without changing locomotor activity. Pre-treatment of imipramine inhibited the LPS-induced elevation of pro-inflammation cytokine levels. Interestingly, imipramine enhanced the gene expression of IL-10 in acute phase in the hippocampus. In primary astrocytes, imipramine enhanced LPS-induced IL-10 expression. Importantly, inhibition of NF-κB with PDTC, a potent NF-κB inhibitor, abolished LPS-induced IL-10 expression. Imipramine increased expression of MEF2D, a critical regulator of IL-10 gene expression, and silencing MEF2D decreased imipramine-enhanced IL-10 mRNA expression.
We revealed that imipramine shows anti-inflammatory effects in the mouse hippocampus and cultured astrocytes, and enhances IL-10 expression in astrocytes. The imipramine-induced IL-10 production in the brain may induce an antidepressant effect. We also elucidated that NF-κB and MEF2D are critical factors for imipramine-mediated IL-10 expression in primary astrocytes. These findings advance the understanding of antidepressant drug action for the treatment of MDD patients.
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