RT journal article
T1 Origin and consequences of brain Toll-like receptor 4 pathway stimulation in an experimental model of depression
A1 Gárate, Itziar
A1 García-Bueno, Borja
A1 Madrigal, José Luis
A1 Bravo García, Lidia
A1 Berrocoso Domínguez, Esther María
A1 Caso, Javier R.
A1 Micó Segura, Juan Antonio
A1 Leza, Juan Carlos
A2 Neurociencias
AB 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.
PB BMC
SN 1742-2094
YR 2011
FD 2011-11-03
LK http://hdl.handle.net/10498/30121
UL http://hdl.handle.net/10498/30121
LA eng
DS Repositorio Institucional de la Universidad de Cádiz
RD 10-may-2026