Dimethyl Fumarate Protects Neural Stem/Progenitor Cellsand Neurons from Oxidative Damage through Nrf2-ERK1/2 MAPK Pathway

International Journal of Molecular Sciences

Steven K. Lundy¹  Sophina Taitano¹  Qi Wu²  Qin Wang²  Yang Mao-Draayer²  Sergei Chuikov²  Joseph M. Corey²  Arjun Rastogi³  Samuel J. Tuck³ 

[1] Department of Internal Medicine, Division of Rheumatology, University of Michigan Medical School, Ann Arbor, MI 48109-2200, USA;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;Geriatrics Research, Education, and Clinical Center (GRECC), VA Ann Arbor Healthcare Center, Ann Arbor, MI 48109-2200, USA;

关键词: multiple sclerosis (MS);    neural stem/progenitor cells (NPCs);    dimethyl fumarate (DMF);    MAPK;    oxidative stress;    neuroprotection;   

DOI  :  10.3390/ijms160613885

来源: DOAJ

【 摘 要 】

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 acidesters (FAE), containing the active metabolite dimethyl fumarate (DMF). Although BG-12 showed remarkable efficacy in lowering relapse rates in clinical trials, its mechanismof 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. DMFalso 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).

【 授权许可】

Unknown