Abstract
BackgroundThere 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.MethodsAdult 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.ResultsCMS 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.ConclusionsOur 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.
Highlights
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
The present work points to a role for bacterial translocation and subsequent Toll-like receptor 4 (TLR-4) pathway stimulation in the neuroinflammation induced by an experimental model of depression
Our results demonstrate for the first time that the Toll-like receptors (TLRs)-4 signaling pathway becomes activated in brain cortex of rats exposed to an animal model of depression
Summary
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. A matter of special relevance is that, the brain has long been considered to be an “immune-privileged” organ, this immune status is far from absolute, especially when blood-brain barrier (BBB) structure or function may be affected, as is the case after stress exposure in animal models of depression or in humans with depression [8,9,10,11,12]. The brain monitors peripheral immune responses by several means acting in parallel [6]: some involve locally produced cytokines or pro-inflammatory cytokine transporters at the BBB and cells surrounding the perivascular space; in another humoral pathway, Toll-like receptors (TLRs) on macrophage-like cells residing in the CNS respond to circulating pathogen components by producing pro-inflammatory cytokines and other pro-inflammatory mediators. The discovery that immune cells, and neurons, astrocytes and resident microglia express a large majority of the already discovered 10 TLRs has challenged the way neuroscience explains the role of the immune system in the brain and, as a result, the view of the brain as an immune privileged organ has been re-evaluated
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