title: Dimethyl Fumarate Induces Glutathione Recycling by Upregulation of Glutathione Reductase.
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 neuroprotectionin 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 ofE. coliRNase 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.
authors.affiliation: Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn ) and Department of Neurology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Hoffmann
authors.affiliation: Department of Neurology, Heinrich Heine Universität Düsseldorf, Düsseldorf, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Dietrich
authors.affiliation: Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn ) and Department of Neurology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
authors.forename: Ann-Kathrin
authors.initials: AK
authors.lastname: Herrmann
authors.affiliation: Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn ) and Department of Neurology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
authors.forename: Teresa
authors.initials: T
authors.lastname: Schacht
authors.affiliation: Department of Neurology, Heinrich Heine Universität Düsseldorf, Düsseldorf, Germany.
authors.forename: Philipp
authors.identifier: 0000-0001-7987-658X
authors.initials: P
authors.lastname: Albrecht
authors.affiliation: Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn ) and Department of Neurology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
authors.forename: Axel
authors.identifier: 0000-0002-8774-0057
authors.initials: A
authors.lastname: Methner
mesh_terms: D000818:Animals; D002460:Cell Line; D000069462:Dimethyl Fumarate / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism*; D005980:Glutathione Reductase / Q000096:biosynthesis*; D015151:Immunoblotting; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D014162:Transfection; D015854:Up-Regulation
chemical_list: D007166:Immunosuppressive Agents; D005980:Glutathione Reductase; D000069462:Dimethyl Fumarate; D005978:Glutathione