The US FDA-Approved Drug Dimethyl Fumarate, an Nrf2 Activator, for Treating Multiple Sclerosis: The Mechanisms of Action Revisited

Dimethyl fumarate, a potent Nrf2 activator and antioxidant-inducing compound, has been approved by the US Food and Drug Administration (FDA) as a first-line drug for treating relapsing forms of multiple sclerosis (MS). Two latest studies published in Nat Commun demonstrated that the efficacy of the drug in treating MS may be associated with increased reactive oxygen species production instead. REFERENCES Rothstein JD. Edaravone: a new drug approved for ALS. Cell 2017; 171(4):725. doi: https://dx.doi.org/10.1016/j.cell.2017.10.011. Ashrafian H, Czibik G, Bellahcene M, Aksentijevic D, Smith AC, Mitchell SJ, et al. Fumarate is cardioprotective via activation of the Nrf2 antioxidant pathway. Cell Metab 2012; 15(3):361–71. doi: https://dx.doi.org/10.1016/j.cmet.2012.01.017. Gold R, Kappos L, Arnold DL, Bar-Or A, Giovannoni G, Selmaj K, et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med 2012; 367(12):1098–107. doi: https://dx.doi.org/10.1056/NEJMoa1114287. Schulze-Topphoff U, Varrin-Doyer M, Pekarek K, Spencer CM, Shetty A, Sagan SA, et al. Dimethyl fumarate treatment induces adaptive and innate immune modulation independent of Nrf2. Proc Natl Acad Sci USA 2016; 113(17):4777–82. doi: https://dx.doi.org/10.1073/pnas.1603907113. Kornberg MD, Bhargava P, Kim PM, Putluri V, Snowman AM, Putluri N, et al. Dimethyl fumarate targets GAPDH and aerobic glycolysis to modulate immunity. Science 2018; 360(6387):449–53. doi: https://dx.doi.org/10.1126/science.aan4665. Carlstrom KE, Ewing E, Granqvist M, Gyllenberg A, Aeinehband S, Enoksson SL, et al. Therapeutic efficacy of dimethyl fumarate in relapsing-remitting multiple sclerosis associates with ROS pathway in monocytes. Nat Commun 2019; 10(1):3081. doi: https://dx.doi.org/10.1038/s41467-019-11139-3. Luckel C, Picard F, Raifer H, Campos Carrascosa L, Guralnik A, Zhang Y, et al. IL-17+ CD8+ T cell suppression by dimethyl fumarate associates with clinical response in multiple sclerosis. Nat Commun 2019; 10(1):5722. doi: https://dx.doi.org/10.1038/s41467-019-13731-z.