Inflammatory mechanisms and vulnerability for major depression: from animal models to drug treatment

Abstract

Major depressive disorder (MDD) is a common disorder that represents a leading cause of disability in the world. It is thought to originate from the interaction between susceptibility genes and environmental events, such as stress, to which an individual can be exposed in different moments of life. One of the major problems of depression is the relevant percentage of patients who do not show an adequate response to antidepressant therapy, as well as the high rate of relapse. Growing evidence suggest that the activation of the inflammatory/immune system contributes to the pathogenesis of depression. Indeed, depressed patients exhibit increased levels of inflammatory markers in both the periphery and the brain, and high comorbidity exists between major depression and diseases associated with inflammatory alterations. In order to characterize the link between depression and inflammation, the aim of the present study was on one hand, to evaluate the effect of antidepressant treatment on systems that might be relevant for the relationship and mutual modulation of depression and inflammation. Indeed, since depression can be considered a functional disease characterized by an impairment in coping mechanisms, LPS administration was used as an inflammatory challenge to investigate how the pharmacological treatment might affect brain responsiveness under a challenging condition. Specifically, male rats were treated for 21 days with agomelatine and they were then challenged with LPS. Animals were sacrificed after 2, 6, or 24 h from the challenge, in order to study the temporal progression of the inflammatory response mediated by LPS injection. We found that agomelatine significantly reduced the LPS-induced up-regulation of interleukin-1b and interleukin-6 in different brain regions as well as at peripheral level. Moreover, pre-treatment with the antidepressant was also able to interfere with mechanisms responsible for microglia activation following LPS injection and to modulate the expression of kynurenine pathway enzymes, which may also represent important mediators for inflammation-related depression. We also investigated if genetic susceptibility to depression was associated with changes of the immune/inflammatory system. Indeed, since mood disorders originate from the interaction between environmental factors and a vulnerable genetic background, we aim to establish if the deletion of serotonin transporter (SERT) gene, a susceptibility gene for depression, was associated with altered expression of inflammatory markers under basal conditions. Secondly, we investigated the functional consequences of exposing these animals to an inflammatory challenge with LPS, which may precipitate the depressive phenotype. We found that animals with deletion of the SERT gene have, under basal conditions, enhanced levels of circulating immune proteins and increased expression of IL-1b in the hippocampus. Moreover, we found that genetic deletion of SERT gene in rats was associated with alterations of pro-inflammatory cytokines and markers of microglia activation following the immune challenge.