Origin and consequences of brain Toll-like receptor 4 pathway stimulation in an experimental model of depression
<p>Abstract</p> <p>Background</p> <p>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...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2011-11-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | http://www.jneuroinflammation.com/content/8/1/151 |
| _version_ | 1818552727956881408 |
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| author | Madrigal José LM García-Bueno Borja Gárate Iciar Bravo Lidia Berrocoso Esther Caso Javier R Micó Juan A Leza Juan C |
| author_facet | Madrigal José LM García-Bueno Borja Gárate Iciar Bravo Lidia Berrocoso Esther Caso Javier R Micó Juan A Leza Juan C |
| author_sort | Madrigal José LM |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>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.</p> <p>Methods</p> <p>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.</p> <p>Results</p> <p>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, PGE<sub>2 </sub>and lipid peroxidation levels and reduced levels of the anti-inflammatory prostaglandin 15d-PGJ<sub>2 </sub>in brain tissue. Intestinal decontamination reduced brain levels of the pro-inflammatory parameters and increased 15d-PGJ<sub>2</sub>, however this did not affect depressive-like behavior induced by CMS.</p> <p>Conclusions</p> <p>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.</p> |
| first_indexed | 2024-12-12T09:16:57Z |
| format | Article |
| id | doaj.art-237b0bfbc81540daab14cbced3632c50 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-12-12T09:16:57Z |
| publishDate | 2011-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-237b0bfbc81540daab14cbced3632c502022-12-22T00:29:21ZengBMCJournal of Neuroinflammation1742-20942011-11-018115110.1186/1742-2094-8-151Origin and consequences of brain Toll-like receptor 4 pathway stimulation in an experimental model of depressionMadrigal José LMGarcía-Bueno BorjaGárate IciarBravo LidiaBerrocoso EstherCaso Javier RMicó Juan ALeza Juan C<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Methods</p> <p>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.</p> <p>Results</p> <p>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, PGE<sub>2 </sub>and lipid peroxidation levels and reduced levels of the anti-inflammatory prostaglandin 15d-PGJ<sub>2 </sub>in brain tissue. Intestinal decontamination reduced brain levels of the pro-inflammatory parameters and increased 15d-PGJ<sub>2</sub>, however this did not affect depressive-like behavior induced by CMS.</p> <p>Conclusions</p> <p>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.</p>http://www.jneuroinflammation.com/content/8/1/151neuroinflammationchronic mild stressdepressioninnate immunityTLR-4LPS |
| spellingShingle | Madrigal José LM García-Bueno Borja Gárate Iciar Bravo Lidia Berrocoso Esther Caso Javier R Micó Juan A Leza Juan C Origin and consequences of brain Toll-like receptor 4 pathway stimulation in an experimental model of depression Journal of Neuroinflammation neuroinflammation chronic mild stress depression innate immunity TLR-4 LPS |
| title | Origin and consequences of brain Toll-like receptor 4 pathway stimulation in an experimental model of depression |
| title_full | Origin and consequences of brain Toll-like receptor 4 pathway stimulation in an experimental model of depression |
| title_fullStr | Origin and consequences of brain Toll-like receptor 4 pathway stimulation in an experimental model of depression |
| title_full_unstemmed | Origin and consequences of brain Toll-like receptor 4 pathway stimulation in an experimental model of depression |
| title_short | Origin and consequences of brain Toll-like receptor 4 pathway stimulation in an experimental model of depression |
| title_sort | origin and consequences of brain toll like receptor 4 pathway stimulation in an experimental model of depression |
| topic | neuroinflammation chronic mild stress depression innate immunity TLR-4 LPS |
| url | http://www.jneuroinflammation.com/content/8/1/151 |
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