title: Fumarates promote cytoprotection of central nervous system cells against oxidative stress via the nuclear factor (erythroid-derived 2)-like 2 pathway.
abstract: Oxidative stress is central to the pathology of several neurodegenerative diseases, including multiple sclerosis, and therapeutics designed to enhance antioxidant potential could have clinical value. The objective of this study was to characterize the potential direct neuroprotective effects of dimethyl fumarate (DMF) and its primary metabolite monomethyl fumarate (MMF) on cellular resistance to oxidative damage in primary cultures of central nervous system (CNS) cells and further explore the dependence and function of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway in this process. Treatment of animals or primary cultures of CNS cells with DMF or MMF resulted in increased nuclear levels of active Nrf2, with subsequent up-regulation of canonical antioxidant target genes. DMF-dependent up-regulation of antioxidant genes in vivo was lost in mice lacking Nrf2 [Nrf2(-/-)]. DMF or MMF treatment increased cellular redox potential, glutathione, ATP levels, and mitochondrial membrane potential in a concentration-dependent manner. Treating astrocytes or neurons with DMF or MMF also significantly improved cell viability after toxic oxidative challenge in a concentration-dependent manner. This effect on viability was lost in cells that had eliminated or reduced Nrf2. These data suggest that DMF and MMF are cytoprotective for neurons and astrocytes against oxidative stress-induced cellular injury and loss, potentially via up-regulation of an Nrf2-dependent antioxidant response. These data also suggest DMF and MMF may function through improving mitochondrial function. The clinical utility of DMF in multiple sclerosis is being explored through phase III trials with BG-12, which is an oral therapeutic containing DMF as the active ingredient.
authors.affiliation: Biogen Idec, 14 Cambridge Center, Cambridge, MA 02142, USA. robert.scannevin@biogenidec.com
authors.forename: Robert H
authors.initials: RH
authors.lastname: Scannevin
authors.forename: Sowmya
authors.initials: S
authors.lastname: Chollate
authors.forename: Mi-young
authors.initials: MY
authors.lastname: Jung
authors.forename: Melanie
authors.initials: M
authors.lastname: Shackett
authors.forename: Hiral
authors.initials: H
authors.lastname: Patel
authors.forename: Pradeep
authors.initials: P
authors.lastname: Bista
authors.forename: Weike
authors.initials: W
authors.lastname: Zeng
authors.forename: Sarah
authors.initials: S
authors.lastname: Ryan
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Matvey
authors.initials: M
authors.lastname: Lukashev
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Rhodes
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002490:Central Nervous System / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D019610:Cytoprotection / Q000187:drug effects / Q000235:genetics*; D005650:Fumarates / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000172:deficiency / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*
chemical_list: D005650:Fumarates; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; C495636:Nfe2l2 protein, mouse