title: Lipopolysaccharide repeated challenge followed by chronic mild stress protocol introduces a combined model of depression in rats: reversibility by imipramine and pentoxifylline.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
authors.forename: Al-Shaimaa A
authors.initials: AS
authors.lastname: Elgarf
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Ain Shams University, Cairo, Egypt; Clinical Pharmacology Unit, Faculty of Medicine, Ain Shams University, Cairo, Egypt. Electronic address: sawsanaf2005@yahoo.com.
authors.forename: Sawsan
authors.initials: S
authors.lastname: Aboul-Fotouh
authors.affiliation: Department of Histology, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
authors.forename: Hadwa A
authors.initials: HA
authors.lastname: Abd-Alkhalek
authors.affiliation: Clinical Pharmacology Unit, Faculty of Medicine, Ain Shams University, Cairo, Egypt; Otto-von-Guericke University Magdeburg, Germany.
authors.forename: Mohamed
authors.initials: M
authors.lastname: El Tabbal
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Ain Shams University, Cairo, Egypt; Clinical Pharmacology Unit, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
authors.forename: Ahmed N
authors.initials: AN
authors.lastname: Hassan
authors.affiliation: Department of Medical Biochemistry, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
authors.forename: Samar K
authors.initials: SK
authors.lastname: Kassim
authors.affiliation: Department of Histology, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
authors.forename: Gehad A
authors.initials: GA
authors.lastname: Hammouda
authors.affiliation: Department of Histology, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
authors.forename: Kawthar A
authors.initials: KA
authors.lastname: Farrag
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Ain Shams University, Cairo, Egypt; Clinical Pharmacology Unit, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
authors.forename: Ahmed M
authors.initials: AM
authors.lastname: Abdel-tawab
mesh_terms: D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects*; D003345:Corticosterone / Q000097:blood; D003863:Depression / Q000150:complications / Q000188:drug therapy*; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects; D006624:Hippocampus / Q000378:metabolism; D007099:Imipramine / Q000494:pharmacology / Q000627:therapeutic use*; D007737:Kynurenine / Q000378:metabolism; D008070:Lipopolysaccharides / Q000009:adverse effects*; D008297:Male; D010431:Pentoxifylline / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D013315:Stress, Psychological / Q000150:complications / Q000188:drug therapy*; D014364:Tryptophan / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000097:blood
chemical_list: D000929:Antidepressive Agents, Tricyclic; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D007737:Kynurenine; D014364:Tryptophan; D007099:Imipramine; D010431:Pentoxifylline; D003345:Corticosterone
keywords: Bacterial lipopolysaccharide; Chronic mild stress; Forced swimming test; Hippocampal TNF-α; Indoleamine 2,3-dioxygenase enzyme; Kynurenine/tryptophan ratio