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Open Access Highly Accessed Research

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

Iciar Gárate145, Borja García-Bueno145, José LM Madrigal145, Lidia Bravo34, Esther Berrocoso34, Javier R Caso245, Juan A Micó34 and Juan C Leza145*

Author Affiliations

1 Department of Pharmacology, Faculty of Medicine, Universidad Complutense, Madrid 28040, Spain

2 Department of Psychiatry, Faculty of Medicine, Universidad Complutense, Madrid 28040, Spain

3 Department of Neurosciences, Faculty of Medicine, Universidad de Cádiz, Cádiz 11003, Spain

4 Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain

5 Instituto de Investigación Sanitaria Hospital 12 de Octubre, Madrid 28026, Spain

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Journal of Neuroinflammation 2011, 8:151  doi:10.1186/1742-2094-8-151

Published: 3 November 2011

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.

Keywords:
neuroinflammation; chronic mild stress; depression; innate immunity; TLR-4; LPS