title: Effects of dimethyl fumarate on neuroprotection and immunomodulation.
abstract: BACKGROUND
  Neuronal degeneration in multiple sclerosis has been linked to oxidative stress. Dimethyl fumarate is a promising novel oral therapeutic option shown to reduce disease activity and progression in patients with relapsing-remitting multiple sclerosis. These effects are presumed to originate from a combination of immunomodulatory and neuroprotective mechanisms. We aimed to clarify whether neuroprotective concentrations of dimethyl fumarate have immunomodulatory effects.
  
  
  RESULTS
  We determined time- and concentration-dependent effects of dimethyl fumarate and its metabolite monomethyl fumarate on viability in a model of endogenous neuronal oxidative stress and clarified the mechanism of action by quantitating cellular glutathione content and recycling, nuclear translocation of transcription factors, and the expression of antioxidant genes. We compared this with changes in the cytokine profiles released by stimulated splenocytes measured by ELISPOT technology and analyzed the interactions between neuronal and immune cells and neuronal function and viability in cell death assays and multi-electrode arrays. Our observations show that dimethyl fumarate causes short-lived oxidative stress, which leads to increased levels and nuclear localization of the transcription factor nuclear factor erythroid 2-related factor 2 and a subsequent increase in glutathione synthesis and recycling in neuronal cells. Concentrations that were cytoprotective in neuronal cells had no negative effects on viability of splenocytes but suppressed the production of proinflammatory cytokines in cultures from C57BL/6 and SJL mice and had no effects on neuronal activity in multi-electrode arrays.
  
  
  CONCLUSIONS
  These results suggest that immunomodulatory concentrations of dimethyl fumarate can reduce oxidative stress without altering neuronal network activity.
authors: Department of Neurology, Heinrich-Heine-University Düsseldorf, Medical Faculty, Düsseldorf 40225, Germany. axel.methner@gmail.com.
authors: Philipp
authors: P
authors: Albrecht
authors: Imane
authors: I
authors: Bouchachia
authors: Norbert
authors: N
authors: Goebels
authors: Nadine
authors: N
authors: Henke
authors: Harald H
authors: HH
authors: Hofstetter
authors: Andrea
authors: A
authors: Issberner
authors: Zsuzsa
authors: Z
authors: Kovacs
authors: Jan
authors: J
authors: Lewerenz
authors: Dmitrij
authors: D
authors: Lisak
authors: Pamela
authors: P
authors: Maher
authors: Anne-Kathrin
authors: AK
authors: Mausberg
authors: Kim
authors: K
authors: Quasthoff
authors: Corinna
authors: C
authors: Zimmermann
authors: Hans-Peter
authors: HP
authors: Hartung
authors: Axel
authors: A
authors: Methner
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D000069462:Dimethyl Fumarate; D005260:Female; D005650:Fumarates / Q000494:pharmacology*; D056747:Immunomodulation / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D016896:Treatment Outcome
chemical_list: D005650:Fumarates; D018696:Neuroprotective Agents; D000069462:Dimethyl Fumarate