title: Dimethyl Fumarate Protects Neural Stem/Progenitor Cells and Neurons from Oxidative Damage through Nrf2-ERK1/2 MAPK Pathway.
abstract: Multiple sclerosis (MS) is the most common multifocal inflammatory demyelinating disease of the central nervous system (CNS). Due to the progressive neurodegenerative nature of MS, developing treatments that exhibit direct neuroprotective effects are needed. Tecfidera™ (BG-12) is an oral formulation of the fumaric acid esters (FAE), containing the active metabolite dimethyl fumarate (DMF). Although BG-12 showed remarkable efficacy in lowering relapse rates in clinical trials, its mechanism of action in MS is not yet well understood. In this study, we reported the potential neuroprotective effects of dimethyl fumarate (DMF) on mouse and rat neural stem/progenitor cells (NPCs) and neurons. We found that DMF increased the frequency of the multipotent neurospheres and the survival of NPCs following oxidative stress with hydrogen peroxide (H2O2) treatment. In addition, utilizing the reactive oxygen species (ROS) assay, we showed that DMF reduced ROS production induced by H2O2. DMF also decreased oxidative stress-induced apoptosis. Using motor neuron survival assay, DMF significantly promoted survival of motor neurons under oxidative stress. We further analyzed the expression of oxidative stress-induced genes in the NPC cultures and showed that DMF increased the expression of transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2) at both levels of RNA and protein. Furthermore, we demonstrated the involvement of Nrf2-ERK1/2 MAPK pathway in DMF-mediated neuroprotection. Finally, we utilized SuperArray gene screen technology to identify additional anti-oxidative stress genes (Gstp1, Sod2, Nqo1, Srxn1, Fth1). Our data suggests that analysis of anti-oxidative stress mechanisms may yield further insights into new targets for treatment of multiple sclerosis (MS).
authors.affiliation: Department of Neurology, University of Michigan Medical School, 4015 Alfred Taubman Biomedical Sciences Research Building, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA. qinwang@umich.edu.
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Neurology, University of Michigan Medical School, 4015 Alfred Taubman Biomedical Sciences Research Building, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA. schuikov@umich.edu.
authors.forename: Sergei
authors.initials: S
authors.lastname: Chuikov
authors.affiliation: Department of Internal Medicine, Division of Rheumatology, University of Michigan Medical School, Ann Arbor, MI 48109-2200, USA. sophinat@umich.edu.
authors.forename: Sophina
authors.initials: S
authors.lastname: Taitano
authors.affiliation: Department of Neurology, University of Michigan Medical School, 4015 Alfred Taubman Biomedical Sciences Research Building, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA. qinwang@umich.edu.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Geriatrics Research, Education, and Clinical Center (GRECC), VA Ann Arbor Healthcare Center, Ann Arbor, MI 48109-2200, USA. arastogi729@gmail.com.
authors.forename: Arjun
authors.initials: A
authors.lastname: Rastogi
authors.affiliation: Geriatrics Research, Education, and Clinical Center (GRECC), VA Ann Arbor Healthcare Center, Ann Arbor, MI 48109-2200, USA. samtuck@umich.edu.|Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109-2200, USA. samtuck@umich.edu.
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Tuck
authors.affiliation: Department of Neurology, University of Michigan Medical School, 4015 Alfred Taubman Biomedical Sciences Research Building, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA. coreyj@umich.edu.|Geriatrics Research, Education, and Clinical Center (GRECC), VA Ann Arbor Healthcare Center, Ann Arbor, MI 48109-2200, USA. coreyj@umich.edu.|Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109-2200, USA. coreyj@umich.edu.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Corey
authors.affiliation: Department of Internal Medicine, Division of Rheumatology, University of Michigan Medical School, Ann Arbor, MI 48109-2200, USA. sklundy@umich.edu.|Graduate Program in Immunology, Program in Biomedical Sciences, University of Michigan Medical School, Ann Arbor, MI 48109-2200, USA. sklundy@umich.edu.
authors.forename: Steven K
authors.initials: SK
authors.lastname: Lundy
authors.affiliation: Department of Neurology, University of Michigan Medical School, 4015 Alfred Taubman Biomedical Sciences Research Building, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA. maodraay@umich.edu.
authors.forename: Yang
authors.initials: Y
authors.lastname: Mao-Draayer
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002478:Cells, Cultured; D002642:Chick Embryo; D000069462:Dimethyl Fumarate / Q000494:pharmacology*; D005260:Female; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D058953:Neural Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D007166:Immunosuppressive Agents; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; D016877:Oxidants; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D000069462:Dimethyl Fumarate
keywords: MAPK; dimethyl fumarate (DMF); multiple sclerosis (MS); neural stem/progenitor cells (NPCs); neuroprotection; oxidative stress