Effects Mediated by Dimethyl Fumarate on In Vitro Oligodendrocytes: Implications in Multiple Sclerosis

Abstract

Background: Dimethyl fumarate (DMF) is a drug currently in use in oral therapy for the treatment of relapsing-remitting multiple sclerosis (RRMS) due to its immunomodulatory and neuroprotective effects. The mechanisms by which DMF exerts its therapeutic effects in MS and in particular its influence on the oligodendrocytes (OLs) survival or differentiation have not yet been fully understood. Methods: Characterization of Oli neu cells was performed by immunocytochemistry and RT-PCR. The effect of DMF on cell proliferation and morphology was assessed by MTT assay, trypan blue staining, RT-PCR and Western blot analysis. The antioxidant and anti-inflammatory properties of DMF were analysed by ROS detection through DCFDA staining and lipid content analysis by Oil Red O staining and TLC. Results: DMF has been observed to induce a slowdown of cell proliferation, favoring the oligodendrocyte lineage cells (OLCs) differentiation. DMF has an antioxidant effect and is able to modify the lipid content even after the LPS-mediated inflammatory stimulus in Oli neu cells. Conclusions: The results obtained confirm that DMF has anti-inflammatory and antioxidant effects also on Oli neu cells. Interestingly, it appears to promote the OLCs differentiation towards mature and potentially myelinating cells.

Pharmacological modulation of inflammatory oligodendrocyte progenitor cells using three multiple sclerosis disease modifying therapies in vitro

“…Instead, CDB had a mild proliferative effect in the live cell imaging studies, though this effect was not detectable in our differentiation assays – possibly due to a lower sensitivity of the immunocytochemistry approach. DMF, on the other hand, inhibits OPC proliferation, as has been reported in other cell types [ [14] , [15] , [16] ]. However, we were unable to replicate reports that DMF promotes OPC differentiation, though this could be explained by the use of primary OPCs in this experiment versus the Oli-neu cell line in published data [ 14 ].…”

“…DMF, on the other hand, inhibits OPC proliferation, as has been reported in other cell types [ [14] , [15] , [16] ]. However, we were unable to replicate reports that DMF promotes OPC differentiation, though this could be explained by the use of primary OPCs in this experiment versus the Oli-neu cell line in published data [ 14 ]. Similarly, to DMF, IFN-β also reduced OPC proliferation and differentiation.…”

“…Under basal conditions, DMF promoted the differentiation of neural progenitor cells to the oligodendrocyte lineage [ 13 ]. In the Oli-neu cell line, DMF suppressed proliferation and promoted differentiation [ 14 ], in line with studies showing anti-proliferative effects of DMF in tumor cells and lymphocytes [ 15 , 16 ]. It should be noted that the clinical benefits of DMF have long been attributed to its metabolite monomethylfumarate (MMF), as DMF is rapidly converted to MMF in vivo [ 17 ] .…”