title: The Neuroprotective Effect of Dimethyl Fumarate in an MPTP-Mouse Model of Parkinson's Disease: Involvement of Reactive Oxygen Species/Nuclear Factor-κB/Nuclear Transcription Factor Related to NF-E2.
abstract: Oxidative stress plays a key role in Parkinson disease (PD), and nuclear transcription factor related to NF-E2 (Nrf-2) is involved in neuroprotection against PD. The aim of the present study was to investigate a role for nuclear factor-κB (NF-κB)/Nrf-2 in the neurotherapeutic action of dimethyl fumarate (DMF) in a mouse model of PD and in vitro in SHSY-5Y cells.
  
  
  
  Daily oral gavage of DMF (10, 30, and 100 mg/kg) significantly reduced neuronal cell degeneration of the dopaminergic tract and behavioral impairments induced by four injections of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Moreover, treatment with DMF prevented dopamine depletion, increased tyrosine hydroxylase and dopamine transporter activities, and also reduced the number of α-synuclein-positive neurons. Furthermore, DMF treatment upregulated the Nrf-2 pathway, increased NeuN+/Nrf-2+cell number in the striatum, induced activation of manganese superoxide dismutase and heme oxygenase-1, and regulated glutathione levels. Moreover, DMF reduced interleukin 1 levels, cyclooxygenase 2 activity, and nitrotyrosine neuronal nitrite oxide synthase expression. This treatment also modulated microglia activation, restored nerve growth factor levels, and preserved microtubule-associated protein 2 alterations. The protective effects of DMF treatment, via Nrf-2, were confirmed in in vitro studies, through inhibition of Nrf-2 by trigonelline.
  
  
  
  These findings demonstrate that DMF, both in a mouse model of PD and in vitro, provides, via regulation of the NF-κB/Nrf-2 pathway, novel cytoprotective modalities that further augment the natural antioxidant response in neurodegenerative and inflammatory disease models.
  
  
  
  These results support the thesis that DMF may constitute a promising therapeutic target for the treatment of PD. Antioxid. Redox Signal. 27, 453-471.
authors.affiliation: 1 Department of Chemical, Biological, Pharmacological and Environmental Sciences, University of Messina , Messina, Italy .
authors.forename: Michela
authors.initials: M
authors.lastname: Campolo
authors.affiliation: 1 Department of Chemical, Biological, Pharmacological and Environmental Sciences, University of Messina , Messina, Italy .
authors.forename: Giovanna
authors.initials: G
authors.lastname: Casili
authors.affiliation: 1 Department of Chemical, Biological, Pharmacological and Environmental Sciences, University of Messina , Messina, Italy .
authors.forename: Flavia
authors.initials: F
authors.lastname: Biundo
authors.affiliation: 1 Department of Chemical, Biological, Pharmacological and Environmental Sciences, University of Messina , Messina, Italy .
authors.forename: Rosalia
authors.initials: R
authors.lastname: Crupi
authors.affiliation: 1 Department of Chemical, Biological, Pharmacological and Environmental Sciences, University of Messina , Messina, Italy .
authors.forename: Marika
authors.initials: M
authors.lastname: Cordaro
authors.affiliation: 1 Department of Chemical, Biological, Pharmacological and Environmental Sciences, University of Messina , Messina, Italy .|2 Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine , St. Louis, Missouri.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cuzzocrea
authors.affiliation: 1 Department of Chemical, Biological, Pharmacological and Environmental Sciences, University of Messina , Messina, Italy .
authors.forename: Emanuela
authors.initials: E
authors.lastname: Esposito
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000009:adverse effects*; D000284:Administration, Oral; D000818:Animals; D002460:Cell Line; D000069462:Dimethyl Fumarate / Q000008:administration & dosage* / Q000494:pharmacology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000494:pharmacology; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D000069462:Dimethyl Fumarate
keywords: Parkinson's disease; central nervous system; dimethyl fumarate; neurodegeneration