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

• Published in: Pharmacology, biochemistry and behavior Vol. 126; pp. 152 - 162
• Main Authors: Elgarf, Al-Shaimaa A., Aboul-Fotouh, Sawsan, Abd-Alkhalek, Hadwa A., El Tabbal, Mohamed, Hassan, Ahmed N., Kassim, Samar K., Hammouda, Gehad A., Farrag, Kawthar A., Abdel-tawab, Ahmed M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-11-2014
• Subjects: Animals; Antidepressive Agents, Tricyclic - pharmacology; Antidepressive Agents, Tricyclic - therapeutic use; Bacterial lipopolysaccharide; Behavior, Animal - drug effects; Chronic mild stress; Corticosterone - blood; Depression - complications; Depression - drug therapy; Disease Models, Animal; Forced swimming test; Gene Expression - drug effects; Hippocampal TNF-α; Hippocampus - metabolism; Imipramine - pharmacology; Imipramine - therapeutic use; Indoleamine 2,3-dioxygenase enzyme; Kynurenine - metabolism; Kynurenine/tryptophan ratio; Lipopolysaccharides - adverse effects; Male; Pentoxifylline - pharmacology; Pentoxifylline - therapeutic use; Rats; Stress, Psychological - complications; Stress, Psychological - drug therapy; Tryptophan - metabolism; Tumor Necrosis Factor-alpha - biosynthesis; Tumor Necrosis Factor-alpha - blood; Forced swimming test; Bacterial lipopolysaccharide; Hippocampal TNF-α; Chronic mild stress; Kynurenine/tryptophan ratio; Indoleamine 2,3-dioxygenase enzyme
• ISSN: 0091-3057; 1873-5177
• DOI: 10.1016/j.pbb.2014.09.014

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-α pentoxyphylline were investigated.
Wistar rats were exposed to either repeated LPS (50μg/kg i.p.) over 2weeks, CMS protocol for 4weeks or LPS over 2weeks then 4weeks 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.
Animals exposed to LPS/CMS elaborated depressive-like symptoms with significant increase in both serum corticosterone and TNF-α levels compared to those in the saline, LPS or CMS groups. Hippocampal kynurenine/tryptophan ratio and TNF-α 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-α gene expression changes induced by the LPS/CMS protocol.
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.
•Our results solidify the suggested link between depression and immune-inflammatory pathways.•The LPS/CMS model elaborated depressive-like symptoms.•Hippocampal kynurenine/tryptophan ratio and TNF-α gene expression significantly increased in the LPS/CMS model.•Imipramine or pentoxifylline reversed behavioral, neurochemical and TNF-α gene expression changes induced by LPS/CMS protocol.