title: Origin and consequences of brain Toll-like receptor 4 pathway stimulation in an experimental model of depression.
abstract: BACKGROUND
  There is a pressing need to identify novel pathophysiological pathways relevant to depression that can help to reveal targets for the development of new medications. Toll-like receptor 4 (TLR-4) has a regulatory role in the brain's response to stress. Psychological stress may compromise the intestinal barrier, and increased gastrointestinal permeability with translocation of lipopolysaccharide (LPS) from Gram-negative bacteria may play a role in the pathophysiology of major depression.
  
  
  METHODS
  Adult male Sprague-Dawley rats were subjected to chronic mild stress (CMS) or CMS+intestinal antibiotic decontamination (CMS+ATB) protocols. Levels of components of the TLR-4 signaling pathway, of LPS and of different inflammatory, oxidative/nitrosative and anti-inflammatory mediators were measured by RT-PCR, western blot and/or ELISA in brain prefrontal cortex. Behavioral despair was studied using Porsolt's test.
  
  
  RESULTS
  CMS increased levels of TLR-4 and its co-receptor MD-2 in brain as well as LPS and LPS-binding protein in plasma. In addition, CMS also increased interleukin (IL)-1β, COX-2, PGE2 and lipid peroxidation levels and reduced levels of the anti-inflammatory prostaglandin 15d-PGJ2 in brain tissue. Intestinal decontamination reduced brain levels of the pro-inflammatory parameters and increased 15d-PGJ2, however this did not affect depressive-like behavior induced by CMS.
  
  
  CONCLUSIONS
  Our results suggest that LPS from bacterial translocation is responsible, at least in part, for the TLR-4 activation found in brain after CMS, which leads to release of inflammatory mediators in the CNS. The use of Gram-negative antibiotics offers a potential therapeutic approach for the adjuvant treatment of depression.
authors: Department of Pharmacology, Faculty of Medicine, Universidad Complutense, Madrid 28040, Spain.
authors: Iciar
authors: I
authors: Gárate
authors: Borja
authors: B
authors: García-Bueno
authors: José L M
authors: JL
authors: Madrigal
authors: Lidia
authors: L
authors: Bravo
authors: Esther
authors: E
authors: Berrocoso
authors: Javier R
authors: JR
authors: Caso
authors: Juan A
authors: JA
authors: Micó
authors: Juan C
authors: JC
authors: Leza
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D003345:Corticosterone / Q000097:blood; D003863:Depression / Q000503:physiopathology*; D004660:Encephalitis / Q000276:immunology; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D007113:Immunity, Innate; D007422:Intestines / Q000187:drug effects / Q000382:microbiology; D008070:Lipopolysaccharides / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D000072000:NF-KappaB Inhibitor alpha; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology*; D013315:Stress, Psychological; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; C000606206:Nfkbia protein, rat; C498145:Rela protein, rat; D051197:Toll-Like Receptor 4; D051996:Transcription Factor RelA; D000072000:NF-KappaB Inhibitor alpha; D003345:Corticosterone