PMID- 28116039
OWN - NLM
STAT- MEDLINE
DCOM- 20170313
LR  - 20181113
IS  - 1942-0994 (Electronic)
IS  - 1942-0900 (Print)
IS  - 1942-0994 (Linking)
VI  - 2017
DP  - 2017
TI  - Dimethyl Fumarate Induces Glutathione Recycling by Upregulation of Glutathione 
      Reductase.
PG  - 6093903
LID - 10.1155/2017/6093903 [doi]
LID - 6093903
AB  - 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.
FAU - Hoffmann, Christina
AU  - Hoffmann C
AD  - 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.
FAU - Dietrich, Michael
AU  - Dietrich M
AD  - Department of Neurology, Heinrich Heine Universitat Dusseldorf, Dusseldorf, 
      Germany.
FAU - Herrmann, Ann-Kathrin
AU  - Herrmann AK
AD  - 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.
FAU - Schacht, Teresa
AU  - Schacht T
AD  - 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.
FAU - Albrecht, Philipp
AU  - Albrecht P
AUID- ORCID: 0000-0001-7987-658X
AD  - Department of Neurology, Heinrich Heine Universitat Dusseldorf, Dusseldorf, 
      Germany.
FAU - Methner, Axel
AU  - Methner A
AUID- ORCID: 0000-0002-8774-0057
AD  - 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.
LA  - eng
PT  - Journal Article
DEP - 20170101
PL  - United States
TA  - Oxid Med Cell Longev
JT  - Oxidative medicine and cellular longevity
JID - 101479826
RN  - 0 (Immunosuppressive Agents)
RN  - EC 1.8.1.7 (Glutathione Reductase)
RN  - FO2303MNI2 (Dimethyl Fumarate)
RN  - GAN16C9B8O (Glutathione)
SB  - IM
MH  - Animals
MH  - Cell Line
MH  - Dimethyl Fumarate/*pharmacology
MH  - Glutathione/*metabolism
MH  - Glutathione Reductase/*biosynthesis
MH  - Immunoblotting
MH  - Immunosuppressive Agents/*pharmacology
MH  - Mice
MH  - Neurons/*drug effects/*metabolism
MH  - Real-Time Polymerase Chain Reaction
MH  - Transfection
MH  - Up-Regulation
PMC - PMC5237454
COIS- The authors declare that they have no competing interests.
EDAT- 2017/01/25 06:00
MHDA- 2017/03/14 06:00
PMCR- 2017/01/01
CRDT- 2017/01/25 06:00
PHST- 2016/06/15 00:00 [received]
PHST- 2016/11/05 00:00 [revised]
PHST- 2016/11/16 00:00 [accepted]
PHST- 2017/01/25 06:00 [entrez]
PHST- 2017/01/25 06:00 [pubmed]
PHST- 2017/03/14 06:00 [medline]
PHST- 2017/01/01 00:00 [pmc-release]
AID - 10.1155/2017/6093903 [doi]
PST - ppublish
SO  - Oxid Med Cell Longev. 2017;2017:6093903. doi: 10.1155/2017/6093903. Epub 2017 Jan 
      1.