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Review
. 2012 Dec;7(3):218-29.
doi: 10.2174/157488912803252023.

The Nrf2-ARE pathway: a valuable therapeutic target for the treatment of neurodegenerative diseases

Gururaj Joshi  1 , Jeffrey A Johnson
Affiliations
Review

The Nrf2-ARE pathway: a valuable therapeutic target for the treatment of neurodegenerative diseases

Gururaj Joshi et al. Recent Pat CNS Drug Discov. 2012 Dec.

Abstract

Modulation of NF-E2 related factor 2 (Nrf2) has been shown in several neurodegenerative disorders. The overexpression of Nrf2 has become a potential therapeutic avenue for various neurodegenerative disorders such as Parkinson, Amyotrophic lateral sclerosis, and Alzheimer's disease. The expression of phase II detoxification enzymes is governed by the cis-acting regulatory element known as antioxidant response element (ARE). The transcription factor Nrf2 binds to ARE thereby transcribing multitude of antioxidant genes. Keap1, a culin 3-based E3 ligase that targets Nrf2 for degradation, sequesters Nrf2 in cytoplasm. Disruption of Keap1-Nrf2 interaction or genetic overexpression of Nrf2 can increase the endogenous antioxidant capacity of the brain thereby rendering protection against oxidative stress in neurodegenerative disorders. This review primarily focuses on recent patents that target Nrf2 overexpression as a promising therapeutic strategy for the treatment of neurodegenerative disorders.

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Figures

Figure 1
Figure 1
Schematic representation of Keap1-Nrf2 interaction and activation. Under basal conditions Keap1 continuously degrades Nrf2 following ubiquitination. Electrophiles and oxidants directly modify reactive cysteine residues on Keap1 thereby disrupting Keap1-Nrf2 interaction. Nrf2 translocates to nucleus and binds to small Maf protein and transcribes ARE-driven genes.
Figure 2
Figure 2
Example of some of the base compounds that activate Nrf2-ARE Pathway.
See this image and copyright information in PMC

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References

    1. Halliwell B. Role of free radicals in the neurodegenerative diseases: therapeutic implications for antioxidant treatment. Drugs Aging. 2001;18:685–716. - PubMed
    1. Aksenov MY, Aksenova MV, Butterfield DA, Geddes JW, Markesbery WR. Protein oxidation in the brain in Alzheimer’s disease. Neuroscience. 2001;103:373–83. - PubMed
    1. Lovell MA, Gabbita SP, Markesbery WR. Increased DNA oxidation and decreased levels of repair products in Alzheimer’s disease ventricular CSF. J Neurochem. 1999;72:771–6. - PubMed
    1. Halliwell B. Oxidative stress and neurodegeneration: where are we now? J Neurochem. 2006;97:1634–58. - PubMed
    1. Itoh K, Wakabayashi N, Katoh Y, Ishii T, Igarashi K, Engel JD, Yamamoto M. Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev. 1999;13:76–86. - PMC - PubMed

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