Origin and consequences of brain Toll-like receptor 4 pathway stimulation in an experimental model of depression

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,pge2and lipid peroxidation levels and reduced levels of the anti-inflammatory prostaglandin 15d-pgj2in 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. © 2011 gárate et al; licensee biomed central ltd.