Background and purpose: there is a pressing need to identify novel pathophysiologic pathways relevant to depression that reveal targets for the development of new medications and elucidate related biomarkers for the identification and monitoring of potentially responsive patients. One promising development in this regard is the emergence of inflammation as a mechanism that may play a role in neuropsychiatric diseases, including depression.
Recent studies have suggested that depression is accompanied by an increased intestinal permeability which would be related to the inflammatory pathophysiology of the disease.
Thus, we aim to evaluate if the exposure to an experimental model of depression induces an intestinal dysfunction and the following bacterial translocation. Furthermore, it also intends to evaluate if the subsequence activation of the TLR-4 in the brain results in stimulation of the MAPK pathways.
Material and Methods: experimental groups of male Wistar rats (n=10/group) were: a control group and a chronic mild stress (CMS; 3 weeks of stress and two different stressors per day) group.
CMS was used as an experimental model of depression. The behavior was analyzed by means of the Forced Swim Test and the Sucrose Intake Test. The body weight and the plasma corticosterone levels were determined once a week.
The presence of bacteria in mesenteric lymph nodes (MLNs), liver, spleen and blood was studied as well as the plasma LPS levels.
To measure a possible intestinal dysfunction after CMS exposure the mRNA or expression levels in the colon of the enzymes iNOS/NOS-2 and COX-2 and the tight junctions proteins ZO-1 and occludin were studied. Also the levels of immunoglobulin A (IgA) and CCL28 were examined.
In the brain, the expression and/or the mRNA levels of TLR-4 and the phosphorylated (activated) forms of ERK 1/2, p38 and JNK were evaluated as well as the nuclear expression of the transcription factor AP-1 (c-Fos/c-Jun).
Results: there is a presence of bacteria in the MLNs, liver and spleen in the CMS experimental group. The CMS induces an intestinal dysfunction (colonic expression of pro-inflammatory enzymes is increased and IgA levels are decreased). In the brain, there is an induction of the TLR-4 and an increase of the activated forms of ERK 1/2 and p38 resulting in an increased nuclear expression of AP-1 (c-Fos/c-Jun).
Conclusion: our data seem to point out to a role of the intestinal bacteria in the pathophysiology of depression through the MAPK pathways and are in agreement with previous data showing that external stressors to the brain, such as LPS, could activate innate immune receptors aggravating the neuroinflammation and the oxidative/nitrosative damage.
Recent studies have suggested that depression is accompanied by an increased intestinal permeability which would be related to the inflammatory pathophysiology of the disease.
Thus, we aim to evaluate if the exposure to an experimental model of depression induces an intestinal dysfunction and the following bacterial translocation. Furthermore, it also intends to evaluate if the subsequence activation of the TLR-4 in the brain results in stimulation of the MAPK pathways.
Material and Methods: experimental groups of male Wistar rats (n=10/group) were: a control group and a chronic mild stress (CMS; 3 weeks of stress and two different stressors per day) group.
CMS was used as an experimental model of depression. The behavior was analyzed by means of the Forced Swim Test and the Sucrose Intake Test. The body weight and the plasma corticosterone levels were determined once a week.
The presence of bacteria in mesenteric lymph nodes (MLNs), liver, spleen and blood was studied as well as the plasma LPS levels.
To measure a possible intestinal dysfunction after CMS exposure the mRNA or expression levels in the colon of the enzymes iNOS/NOS-2 and COX-2 and the tight junctions proteins ZO-1 and occludin were studied. Also the levels of immunoglobulin A (IgA) and CCL28 were examined.
In the brain, the expression and/or the mRNA levels of TLR-4 and the phosphorylated (activated) forms of ERK 1/2, p38 and JNK were evaluated as well as the nuclear expression of the transcription factor AP-1 (c-Fos/c-Jun).
Results: there is a presence of bacteria in the MLNs, liver and spleen in the CMS experimental group. The CMS induces an intestinal dysfunction (colonic expression of pro-inflammatory enzymes is increased and IgA levels are decreased). In the brain, there is an induction of the TLR-4 and an increase of the activated forms of ERK 1/2 and p38 resulting in an increased nuclear expression of AP-1 (c-Fos/c-Jun).
Conclusion: our data seem to point out to a role of the intestinal bacteria in the pathophysiology of depression through the MAPK pathways and are in agreement with previous data showing that external stressors to the brain, such as LPS, could activate innate immune receptors aggravating the neuroinflammation and the oxidative/nitrosative damage.
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