Abstract
Evidence indicates that adverse experiences in early life may be a factor for immune disturbances leading to the depression in adulthood. Recently, a pivotal role in the pathogenesis of depression has been assigned to the activation of the brain Nod-like receptor pyrin-containing 3 (NLRP3) inflammasome. We investigated the impact of chronic treatment with antidepressant drugs on the behavioral disturbances and the levels of proinflammatory factors in the hippocampus and frontal cortex of adult male rats after prenatal stress exposure. Next, we explored the involvement of the NLRP3 inflammasome-related pathways in the mechanism of antidepressant action. Our study confirmed that chronic antidepressant treatment attenuated depression-like disturbances and exerted an anxiolytic action. All antidepressants diminished the prenatal stress-induced increase in IL-1β in both brain areas, while IL-18 only in the hippocampus. Moreover, tianeptine administration diminished the increase in CCR2 levels in both brain areas, while in the hippocampus, tianeptine, along with venlafaxine CCL2 and iNOS levels. Next, we observed that in the hippocampus, tianeptine and fluoxetine suppressed upregulation of TLR4. Furthermore, venlafaxine suppressed NFкB p65-subunit phosphorylation, while fluoxetine enhanced the IкB level. Importantly, in the hippocampus, all antidepressants normalized evoked by stress changes in caspase-1 level, while tianeptine and venlafaxine also affect the levels of ASC and NLRP3 subunits. Our results provide new evidence that chronic administration of antidepressants exerts anti-inflammatory effects more pronounced in the hippocampus, through suppression of the NLRP3 inflammasome activation. These effects are accompanied by an improvement in the behavioral dysfunctions evoked by prenatal stress.
Highlights
A vast body of evidence suggests that depression is a complex disorder involving molecular, structural, and functional dysfunctions in several brain areas, which makes the biological background of this illness still unclear [1]
In the set of biochemical experiments, we evaluated the impact of tianeptine, venlafaxine, and fluoxetine on the protein expression of the proinflammatory cytokines IL-1β, IL-18, chemokine CC ligand 2 (CCL2), and chemokine CCL2 receptor (CCR2) as well as iNOS levels in the hippocampus and frontal cortex of prenatally stressed male offspring
As we previously demonstrated [38], enhanced immobility time (p < 0.05; 201 ± 4.8 Con vs. 275.16 ± 1.4 PS) and shortened swimming (p < 0.05; 99 ± 4.8 Con vs. 24.83 ± 1.4 PS) and climbing (p < 0.05; 51.5 ± 3.37 Con vs. 16.16 ± 0.74 PS) times were detected in prenatally stressed offspring compared with control offspring, which led to the conclusion that the behavioral disturbances evoked by prenatal stress are long lasting (Table 2)
Summary
A vast body of evidence suggests that depression is a complex disorder involving molecular, structural, and functional dysfunctions in several brain areas, which makes the biological background of this illness still unclear [1]. Among a number of hypotheses of depression, the immune theory postulates that functional changes in the immune system and its mediator cytokines and chemokines may be crucial in the development of this disease [3,4,5]. Chemokine CC ligand 2 (CCL2) and its receptor CC receptor 2. The pleiotropic actions of this chemokine are likely to be relevant to the pathophysiology of psychiatric disorders in adulthood [10] and potentially to the developmental pathogenesis of depression, as suggested by its extensive and dynamic expression during in utero neurodevelopment
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