Inhibitory effect of the antidepressant imipramine on NF-κB-dependent CXCL1 expression in TNFα-exposed astrocytes.

Neuroinflammation is associated with the pathophysiology of various neurodegenerative diseases. Emerging evidence indicates that imipramine, a tricyclic antidepressant commonly used in depressive disorders, exhibits neuroprotective activity partly through anti-inflammatory effects. However, the molecular mechanisms underlying imipramine-mediated anti-inflammatory response are poorly understood. In this study, rat primary cultured astrocytes were used to elucidate the effect of the imipramine on TNFα-induced inflammatory responses. The results clearly demonstrated that imipramine reduced TNFα-induced CXCL1 expression through suppression of NF-κB-dependent CXCL1 promoter activity in primary astrocytes. In addition, we found that imipramine suppressed TNFα-induced phosphorylation of inhibitor of κBα (IκBα) and p65/RelA nuclear factor-κB (NF-κB), as well as the nuclear translocation of p65/RelA in primary cultured astrocytes. Chemotaxis assay demonstrated that astrocyte-derived CXCL1 contributed to migration of BV2 microglial cells toward astrocytes. This response was significantly blocked by treatment of astrocytes with imipramine or NF-κB inhibitor BAY11-7082. This study indicates that the antidepressant imipramine inhibits TNFα-induced CXCL1 expression via down-regulation of NF-κB signaling pathway in astrocytes and suggests that imipramine has a potential as an anti-inflammatory drug.