Efeito antidepressivo do dimetil fumarato em camundongos submetidos ao modelo de estresse crônico imprevisível: envolvimento de mecanismos astrocíticos e microgliais

Abstract

Major Depressive Disorder (MDD) is a highly prevalent psychiatric condition. Many patients are not responsive to conventional pharmacotherapy that modulates the monoaminergic system and even those who are responsive have various adverse effects. Dimethyl fumarate (DMF) is an activator of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, which has antioxidant and anti-inflammatory effects. As several studies demonstrate the involvement of inflammation in the pathophysiology of MDD, the study of DMF in this context shows promising. Thus, the present work aims to investigate the effect of dimethylfumarate on neuroinflammation through the depression model induced by Chronic Unpredictable Mild Stress (CUMS). For this, male mice were exposed to stressful events for 28 days and from the 14th day they received DMF in the doses of 50 and 100 mg / kg or fluoxetine 10 mg / kg or saline, orally; one group was not submitted to CUMS, to be used as a control. On the 29th day, the animals were subjected to behavioral tests to assess locomotor activity (Open Field), depressive-like behavior (Forced swimming, Sucrose preference) and cognitive performance (Y-Maze and Novel Object Recognition) and then had their brains dissected. Microglia and astrocyte markers expressions were evaluated through immunofluorescence analysis and the cytokines TNF-α and IL-Iβ were measured by immunoenzymatic assay in hippocampus. In addition, we performed target prediction, molecular modeling and docking calculations that suggest Kelch-like ECH-associated protein 1 (Keap1) and Hydroxycarboxylic acid receptor 2 (HCAR2) as the probable targets of monomethyl fumarate (DMF active metabolite). CUMS induced anxiety- and depressive-like behaviors, cognitive deficit, decreased astrocyte marker and increased microglia marker, TNF-α and IL-Iβ expression in the hippocampus. These alterations were reversed by DMF. Thus, it is suggested that one of the mechanisms involved in the antidepressant effect of DMF is neuroinflammatory suppression through the HCAR2 signaling pathway. However, more studies must be carried out in order to better understand the molecular mechanisms of this drug.