Neuroprotective effects of dimethyl fumarate against depression-like behaviors via astrocytes and microglia modulation in mice: possible involvement of the HCAR2/Nrf2 signaling pathway

Abstract

We postulated that dimethyl fumarate (DMF), an activator of the Nuclear Factor Erythroid 2-related factor 2 (Nrf2) pathway, exerts neuroprotective effects against depression-like behaviors through astrocytes and microglia modulation. To ascertain our hypothesis and define the mechanistic pathways involved in effect of DMF on neuroinflammation, we used the depression model induced by Chronic Unpredictable Mild Stress (CUMS), in which, the 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. On the 29th day, the animals were subjected to behavioral tests. Microglia (Iba1) and astrocytes (GFAP) markers expressions were evaluated by immunofluorescence analyzes and the cytokines TNF-α and IL-Iβ by immunoenzymatic assay. In addition, computational target prediction, 3D protein structure prediction and docking calculations were performed with monomethyl fumarate (DMF active metabolite) and the Kelch-like ECH associated protein-1 and hydroxycarboxylic acid receptor 2 (HCAR2), which suggested that these could be the probable targets related protective effects. CUMS induced anxiety- and depressive-like behaviors, cognitive deficit, decreased GFAP and increased Iba1, 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 signaling pathway HCAR2 / Nrf2. However, more studies must be performed to better understand the molecular mechanisms of this drug.

Microglial Responses to Stress-Induced Depression: Causes and Consequences

“…Dimethyl fumarate is another anti-inflammatory compound that acts as an antidepressant in the CUMS model of depression. Treatment of mice with dimethyl fumarate reduced proinflammatory cytokine expression as well as microglial immunoreactivity in the hippocampus of the CUMS mice [79].…”