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

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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.

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Abbreviations

Aβ:

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

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Acknowledgments

This work was supported by grants from ‘Stichting Vrienden MS Research,’ The Netherlands, project numbers MS 05-358c (J. van Horssen).

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Authors and Affiliations

  1. Department of Molecular Cell Biology and Immunology, Neuroscience Campus Amsterdam, VU University Medical Center Amsterdam, P.O. Box 7057, 1007 MB, Amsterdam, The Netherlands

    Jamie L. Lim, Helga E. de Vries & Jack van Horssen

  2. Anatomy and Neurosciences, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands

    Micha M. M. Wilhelmus & Benjamin Drukarch

  3. Pathology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands

    Jeroen J. M. Hoozemans

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  1. Jamie L. Lim
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  2. Micha M. M. Wilhelmus
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Correspondence to Jack van Horssen.

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Lim, J.L., Wilhelmus, M.M.M., de Vries, H.E. et al. Antioxidative defense mechanisms controlled by Nrf2: state-of-the-art and clinical perspectives in neurodegenerative diseases. Arch Toxicol 88, 1773–1786 (2014). https://doi.org/10.1007/s00204-014-1338-z

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