title: Dimethyl fumarate attenuates 6-OHDA-induced neurotoxicity in SH-SY5Y cells and in animal model of Parkinson's disease by enhancing Nrf2 activity.
abstract: Oxidative stress is central to the pathology of several neurodegenerative diseases, including Parkinson's disease (PD), and therapeutics designed to enhance antioxidant potential could have clinical value. In this study, we investigated whether dimethyl fumarate (DMF) has therapeutic effects in cellular and animal model of PD, and explore the role of nuclear transcription factor related to NF-E2 (Nrf2) in this process. Treatment of animals and dopaminergic SH-SY5Y cells with DMF resulted in increased nuclear levels of active Nrf2, with subsequent upregulation of antioxidant target genes. The cytotoxicity of 6-hydroxydopamine (6-OHDA) was reduced by pre-treatment with DMF in SH-SY5Y cells. The increase in the reactive oxygen species caused by 6-OHDA treatment was also attenuated by DMF in SH-SY5Y cells. The neuroprotective effects of DMF against 6-OHDA neurotoxicity were dependent on Nrf2, since treatment with Nrf2 siRNA failed to block against 6-OHDA neurotoxicity and induce Nrf2-dependent cytoprotective genes in SH-SY5Y cells. In vivo, DMF oral administration was shown to upregulate mRNA and protein levels of Nrf2 and Nrf2-regulated cytoprotective genes, attenuate 6-OHDA induced striatal oxidative stress and inflammation in C57BL/6 mice. Moreover, DMF ameliorated dopaminergic neurotoxicity in 6-OHDA-induced PD animal models as evidenced by amelioration of locomotor dysfunction, loss in striatal dopamine, and reductions in dopaminergic neurons in the substantia nigra and striatum. Taken together, these data strongly suggest that DMF may be beneficial for the treatment of neurodegenerative diseases like PD.
authors.affiliation: Department of Pharmacology, School of Medicine, Shandong University, Jinan 250012, China.
authors.forename: X
authors.initials: X
authors.lastname: Jing
authors.affiliation: Department of Pharmacology, School of Medicine, Shandong University, Jinan 250012, China.
authors.forename: H
authors.initials: H
authors.lastname: Shi
authors.affiliation: Department of Pharmacy, Jinan Women and Children's Hospital, Jinan 250012, China.
authors.forename: C
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, School of Medicine, Shandong University, Jinan 250012, China.
authors.forename: M
authors.initials: M
authors.lastname: Ren
authors.affiliation: Department of Pharmacology, School of Medicine, Shandong University, Jinan 250012, China.
authors.forename: M
authors.initials: M
authors.lastname: Han
authors.affiliation: Department of Pharmacology, School of Medicine, Shandong University, Jinan 250012, China.
authors.forename: X
authors.initials: X
authors.lastname: Wei
authors.affiliation: Department of Pharmacology, School of Medicine, Shandong University, Jinan 250012, China.
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, School of Medicine, Shandong University, Jinan 250012, China. Electronic address: louhaiyan@sdu.edu.cn.
authors.forename: H
authors.initials: H
authors.lastname: Lou
mesh_terms: D000818:Animals; D061745:Antioxidant Response Elements / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003342:Corpus Striatum / Q000378:metabolism; D000069462:Dimethyl Fumarate; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism; D005650:Fumarates / Q000008:administration & dosage* / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000378:metabolism*; D018384:Oxidative Stress; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism*; D065842:Pars Compacta / Q000378:metabolism; D017382:Reactive Oxygen Species; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic
chemical_list: D005650:Fumarates; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D016627:Oxidopamine; D000069462:Dimethyl Fumarate
keywords: 6-OHDA; Nrf2; Parkinson’s disease; dimethyl fumarate