Effects of fumarates on inflammatory human astrocyte responses and oligodendrocyte differentiation

Objective: Dimethyl fumarate (DMF) is a fumaric acid ester approved for the treatment of relapsing-remitting multiple sclerosis (RRMS). In both the brain and periphery, DMF and its metabolite monomethyl fumarate (MMF) exert anti-inflammatory and antioxidant effects. Our aim was to compare the effects of DMF and MMF on inflammatory and antioxidant pathways within astrocytes, a critical supporting glial cell in the central nervous system (CNS). Direct effects of fumarates on neural progenitor cell (NPC) differentiation toward the oligodendrocyte lineage were also assessed. Methods: Primary astrocyte cultures were derived from both murine and human brains. Following pretreatment with MMF, DMF, or vehicle, astrocytes were stimulated with IL-1 beta for 24 h; gene and microRNA expression were measured by qPCR. Cytokine production and reactive oxygen species (ROS) generation were also measured. NPCs were differentiated into the oligodendrocyte lineage in the presence of fumarates and immunostained using early oligodendrocyte markers. Results: In both murine and human astrocytes, DMF, but not MMF, significantly reduced secretion of IL-6, CXCL10, and CCL2; neither fumarate promoted a robust increase in antioxidant gene expression, although both MMF and DMF prevented intracellular ROS production. Pretreatment with fumarates reduced microRNAs -146a and -155 upon stimulation. In NPC cultures, DMF increased the number of O4 and NG2 cells. Interpretation: These results suggest that DMF, and to a lesser extent MMF, mediates the anti-inflammatory effects within astrocytes. This is supported by recent observations that in the inflamed CNS, DMF may be the active compound mediating the anti-inflammatory effects independent from altered antioxidant gene expression.