Distinct Nrf2 signaling mechanisms of fumaric acid esters and their role in neuroprotection against 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-induced experimental parkinson’s-like disease Academic Article uri icon

Overview

MeSH Major

  • Fumarates
  • NF-E2-Related Factor 2
  • Neuroprotective Agents
  • Parkinsonian Disorders
  • Signal Transduction

abstract

  • Almost two centuries since its first description by James Parkinson, Parkinson's disease (PD) remains an incurable disease with limited symptomatic treatment. The current study provides preclinical evidence that a Food and Drug Administration-approved drug, dimethylfumarate (DMF), and its metabolite monomethylfumarate (MMF) can block nigrostriatal dopaminergic neurodegeneration in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of PD. We elucidated mechanisms by which DMF and its active metabolite MMF activates the redox-sensitive transcription factor nuclear-factor-E2-related factor 2 (Nrf2) to upregulate antioxidant, anti-inflammatory, mitochondrial biosynthetic and cytoprotective genes to render neuroprotection via distinct S-alkylating properties and depletion of glutathione. Our data suggest that targeting Nrf2-mediated gene transcription using MMF rather than DMF is a promising approach to block oxidative stress, neuroinflammation, and mitochondrial dysfunction for therapeutic intervention in PD while minimizing side effects.

publication date

  • June 8, 2016

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC4899530

Digital Object Identifier (DOI)

  • 10.1523/JNEUROSCI.0426-16.2016

PubMed ID

  • 27277809

Additional Document Info

start page

  • 6332

end page

  • 51

volume

  • 36

number

  • 23