Lipopolysaccharide repeated challenge followed by chronic mild stress protocol introduces a combined model of depression in rats: Reversibility by imipramine and pentoxifylline

Objectives: The present study examined the effect of combined exposure to repeated challenge using low doses of lipopolysaccharide (LPS) and chronic mild stress (CMS) together. This combined exposure is thought to expose the animals to more realistic challenges, testable on different levels (behavioral, neurochemical, immunohistochemical and gene expression). The role of glial cells was examined, as well. Additionally, the effects of chronic administration of the tricyclic antidepressant imipramine and the anti-TNF-alpha pentoxyphylline were investigated. Methods: Wistar rats were exposed to either repeated LPS (50 mu g/kg i.p.) over 2 weeks, CMS protocol for 4 weeks or LPS over 2 weeks then 4 weeks of CMS. Two groups of rats were exposed to LPS/CMS protocol and treated with either imipramine or pentoxifylline. Rats were examined for behavioral, neurochemical and gene expression changes. Results: Animals exposed to LPS/CMS elaborated depressive-like symptoms with significant increase in both serum corticosterone and TNF-alpha levels compared to those in the saline, LPS or CMS groups. Hippocampal kynurenine/tryptophan ratio and TNF-alpha gene expression showed significant increase in the LPS/CMS model compared to those in saline, LPS or CMS groups. The immunohistochemical findings scrutinized the topography of the examined effects. Chronic treatment with imipramine or pentoxifylline significantly ameliorated the behavioral, neurochemical, immunohistochemical and TNF-alpha gene expression changes induced by the LPS/CMS protocol. Conclusion: This study gave a clue to the neurobiological processes underlying, at least, the subtypes of depressive disorders. It highlighted the possible interactions between stress and immune-inflammatory pathways in the pathogenesis of depression and suggested a new animal model of depression that addresses these pathways. (C) 2014 Elsevier Inc. All rights reserved.