Program

PO1-1-111

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

 [Introduction]
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.
[Results]
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.
[Discussion]
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.
Advanced Search