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Oxidative Medicine and Cellular Longevity
Volume 2017 (2017), Article ID 6093903, 8 pages
https://doi.org/10.1155/2017/6093903
Research Article

Dimethyl Fumarate Induces Glutathione Recycling by Upregulation of Glutathione Reductase

1Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn2) and Department of Neurology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
2Department of Neurology, Heinrich Heine Universität Düsseldorf, Düsseldorf, Germany

Correspondence should be addressed to Axel Methner

Received 15 June 2016; Revised 5 November 2016; Accepted 16 November 2016; Published 1 January 2017

Academic Editor: Albena Dinkova-Kostova

Copyright © 2017 Christina Hoffmann et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Neuronal degeneration in multiple sclerosis has been linked to oxidative stress. Dimethyl fumarate (DMF) is an effective oral therapeutic option shown to reduce disease activity and progression in patients with relapsing-remitting multiple sclerosis. DMF activates the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) leading to increased synthesis of the major cellular antioxidant glutathione (GSH) and prominent neuroprotection in vitro. We previously demonstrated that DMF is capable of raising GSH levels even when glutathione synthesis is inhibited, suggesting enhanced GSH recycling. Here, we found that DMF indeed induces glutathione reductase (GSR), a homodimeric flavoprotein that catalyzes GSSG reduction to GSH by using NADPH as a reducing cofactor. Knockdown of GSR using a pool of E. coli RNase III-digested siRNAs or pharmacological inhibition of GSR, however, also induced the antioxidant response rendering it impossible to verify the suspected attenuation of DMF-mediated neuroprotection. However, in cystine-free medium, where GSH synthesis is abolished, pharmacological inhibition of GSR drastically reduced the effect of DMF on glutathione recycling. We conclude that DMF increases glutathione recycling through induction of glutathione reductase.