Archives of Toxicology

, Volume 88, Issue 10, pp 1773–1786

Antioxidative defense mechanisms controlled by Nrf2: state-of-the-art and clinical perspectives in neurodegenerative diseases

  • Jamie L. Lim
  • Micha M. M. Wilhelmus
  • Helga E. de Vries
  • Benjamin Drukarch
  • Jeroen J. M. Hoozemans
  • Jack van Horssen
Review Article

DOI: 10.1007/s00204-014-1338-z

Cite this article as:
Lim, J.L., Wilhelmus, M.M.M., de Vries, H.E. et al. Arch Toxicol (2014) 88: 1773. doi:10.1007/s00204-014-1338-z

Abstract

Activation of microglial cells and impaired mitochondrial function are common pathological characteristics of many neurological diseases and contribute to increased generation of reactive oxygen species (ROS). It is nowadays accepted that oxidative damage and mitochondrial dysfunction are key hallmarks of classical neuroinflammatory and neurodegenerative diseases, such as multiple sclerosis, Alzheimer’s disease, Parkinson’s disease and Huntington’s disease. To counteract the detrimental effects of ROS and restore the delicate redox balance in the central nervous system (CNS), cells are equipped with an endogenous antioxidant defense mechanism consisting of several antioxidant enzymes. The production of many antioxidant enzymes is regulated at the transcriptional level by the transcription factor nuclear factor E2-related factor 2 (Nrf2). Although evidence is accumulating that activation of the Nrf2 pathway represents a promising therapeutic approach to restore the CNS redox balance by reducing ROS-mediated neuronal damage in experimental models of neurodegenerative disorders, only a few Nrf2-activating compounds have been tested in a clinical setting. We here provide a comprehensive synopsis on the role of ROS in common neurodegenerative disorders and discuss the therapeutic potential of the Nrf2 pathway.

Keywords

Reactive oxygen species Oxidative stress Neurodegenerative disorders Nrf2 Antioxidant enzymes Free radicals 

Abbreviations

β Amyloid

AD

Alzheimer’s disease

ARE

Antioxidant response elements

BBB

Blood–brain barrier

CNS

Central nervous system

CSF

Cerebrospinal fluid

DMF

Dimethyl fumarate

EAE

Experimental autoimmune encephalomyelitis

HD

Huntington’s disease

HTT

Huntingtin

iNOS

Inducible nitric oxide synthase

Keap1

Kelch-like ECH-associated protein 1

MMF

Monomethyl fumarate

MPTP

1-Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine

MS

Multiple sclerosis

mtDNA

Mitochondrial DNA

NADPH

Nicotinamide adenine dinucleotide phosphate

NOX

Nicotinamide adenine dinucleotide phosphate oxidase

Nrf2

Nuclear factor E2-related factor 2

6-OHDA

6-hydroxydopamine

OxPhos

Oxidative phosphorylation

PERK

Protein kinase RNA-like endoplasmic reticulum kinase

PD

Parkinson’s disease

ROS

Reactive oxygen species

SN

Substantia nigra

tBHQ

Tert-butylhydroquinone

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Jamie L. Lim
    • 1
  • Micha M. M. Wilhelmus
    • 2
  • Helga E. de Vries
    • 1
  • Benjamin Drukarch
    • 2
  • Jeroen J. M. Hoozemans
    • 3
  • Jack van Horssen
    • 1
  1. 1.Department of Molecular Cell Biology and Immunology, Neuroscience Campus AmsterdamVU University Medical Center AmsterdamAmsterdamThe Netherlands
  2. 2.Anatomy and Neurosciences, Neuroscience Campus AmsterdamVU University Medical CenterAmsterdamThe Netherlands
  3. 3.Pathology, Neuroscience Campus AmsterdamVU University Medical CenterAmsterdamThe Netherlands

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