Evaluation of neuroinflammation in an animal model of depression : effect of antidepressant treatment

Introduction - Major depression (MD) is a complex disease that originates from the interaction between a genetic background of susceptibility and environmental factors, such as stress, and characterized by dysfunction of multiple systems including neurotransmitters, hormones, signaling pathways, neurotrophic and neuroplastic molecules. In addition, there is strong evidence that depression is also associated with alterations of the immune/inflammatory system [Dantzer 2008]. On these bases, the purpose of our study was to elucidate the role of inflammation on the generation of anhedonia, one of the core symptoms of MD, and to evaluate the ability of pharmacological intervention in modulating the behavioral-associated inflammatory alterations. Methods - We analyzed the cerebral expression of several mediators of the immune/inflammatory system in rats exposed to the chronic mild stress (CMS) paradigm, a procedure constituted by an unpredictable series of mild stressors (such as water or food deprivation, altered illumination, cage tilting etc), known to induce an anhedonic phenotype [Papp 2012]. Specifically, rats exposed to CMS for two or seven weeks were tested using the sucrose consumption test to assess the insurgence of an anhedonic phenotype and real-time PCR was performed in different brain regions to assess the mRNA levels of inflammatory cytokines (IL-1, IL-6 and TGF-marker of microglia activation (CD11b), kynurenine aminotransferase (KATII) and kynurenine 3-monooxygenase (KMO), two key components of the kynurenine pathway. In addition, to evaluate the impact of antidepressant treatment on anhedonic behaviour and on the different molecular targets, a separate cohort of rats were exposed to CMS and chronically treated with the antidepressant drugs imipramine (10 mg/kg daily by intraperitoneal injection) and agomelatine (40 mg/kg daily by intraperitoneal injection) during the last five weeks of CMS. Results - We found major changes in the dorsal hippocampus, where the levels of the pro-inflammatory cytokines IL-1 and IL-6 were increased only in rats become anhedonic after 2 weeks of CMS (+51% p<0.01 and % +27 p<0.05 vs CTRL) without changes in animals resilient to the stress procedure. A similar profile was observed for the mRNA levels of CD11b (+50%, p<0.05 vs CTRL), conversely, the expression of the anti-inflammatory cytokine TGF- was not affected by 2 weeks of CMS. Interestingly, we also found differences in the modulation of the gene expression between anhedonic animals and stress resilient rats of the enzymes KMO and KATII, suggestive of a dysregulation of the kynurenine pathway. These changes were also observed after longer exposure to CMS. and oth antidepressants were able to normalize not only the pathological phenotype but also to ameliorate the inflammatory changes observed at the molecular level. Conclusions - These data suggest that the immune/inflammatory alterations are not a merely consequence of stress exposure, but they may contribute to the subject’s vulnerability to depression and support the idea that this system may serve as a viable therapeutic target for more effective antidepressant drugs.