Dimethylfumarate Protects from Oxidative Stress by Increasing Glutathione (P02.120)

Abstract

Objective: To evaluate the mechanism of action of dimethylfumarate (DMF), a novel oral therapeutic for the treatment of multiple sclerosis. Background An oral formulation of DMF (BG00012) proved to be effective in patients with relapsing-remitting multiple sclerosis. DMF is known to have both immunomodulatory and cytoprotective effects: It induces lymphocytopenia and a shift from TH1 to TH2 cytokines and it activates the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) leading to elevated cellular glutathione levels and an increased expression of protective genes. Design/Methods: We investigated the role of DMF in oxidative stress in hippocampal HT22 cells, primary cortical cultures and mouse embryonic fibroblasts of wildtype and Nrf2-knockout mice, measured induction of antioxidant proteins, and determined survival and cytokine productions of splenocytes. Results: DMF protected neuronal cells from oxidative stress by elevating intracellular glutathione levels. Protection was concentration- and time-dependent and took at least 24 hours to develop. Shorter incubation reduced cellular glutathione. DMF increased the expression of NQO1, GCL, Prx1 and xCT, all genes involved in defense against oxidative stress containing an antioxidant-response element in their promoter regions. DMF induced transcription from the GCL promoter and enhanced nuclear localization of Nrf2. In line with this, glutathione elevation was abolished in Nrf2-knockout cells. DMF also protected against inhibition of glutathione synthesis by incubation in cystine-free medium or inhibition of glutamate-cysteine ligase indicating enhanced recycling of glutathione. In mouse splenocytes, DMF reduced the anti-CD3 induced production of IFN-gamma, IL1 and IL2, and elevated the production of IL6 at concentrations that were not detrimental. Conclusions: DMF protects neuronal cells from glutathione depletion by Nrf2 driven induction of antioxidant genes and enhanced glutathione recycling at concentrations that reduce the production of TH1 cytokines and elevate IL6 production in splenocytes. Supported by: Biogen Idec. Disclosure: Dr. Albrecht has received research support from Novartis. Dr. Bouchachia has nothing to disclose. Dr. Kovacs has nothing to disclose. Dr. Henke has nothing to disclose. Dr. Zimmermann has nothing to disclose. Dr. Hofstetter has nothing to disclose. Dr. Hartung has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, BioMS, Genzyme Corporation, Merck Serono, Novartis, Sanofi-Aventis and Teva as a speaker and/or consultant. Dr. Methner has nothing to disclose.