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Induction of the Nrf2-driven Antioxidant Response Confers Neuroprotection during Mitochondrial Stress in Vivo
Open accessAbstract
NF-E2 related factor (Nrf2) controls a pleiotropic cellular defense, where multiple antioxidant/detoxification pathways are up-regulated in unison. Although small molecule inducers of Nrf2 activity have been reported to protect neurons in vitro, whether similar pathways can be accessed in vivo is not known. We have investigated whether in vivo toxicity of the mitochondrial complex II inhibitor 3-nitropropionic acid (3-NP) can be attenuated by constitutive and inducible Nrf2 activity. The absence of Nrf2 function in Nrf2(-/-) mice resulted in 3-NP hypersensitivity that became apparent with time and increasing dose, causing motor deficits and striatal lesions on a more rapid time scale than identically treated Nrf2(+/+) and Nrf2(+/-) controls. Striatal succinate dehydrogenase activity, the target of 3-NP, was inhibited to the same extent in all genotypes by a single acute dose of 3-NP, suggesting that brain concentrations of 3-NP were similar. Dietary supplementation with the Nrf2 inducer tert-butylhydroquinone attenuated 3-NP toxicity in Nrf2(+/-) mice, but not Nrf2(-/-), confirming the Nrf2-specific action of the inducer in vivo. Increased Nrf2 activity alone was sufficient to protect animals from 3-NP toxicity because intrastriatal adenovirus-mediated Nrf2 overexpression significantly reduced lesion size compared with green fluorescent protein overexpressing controls. In cultured astrocytes, 3-NP was found to increase Nrf2 activity leading to antioxidant response element-dependent gene expression providing a potential mechanism for the increased sensitivity of Nrf2(-/-) animals to 3-NP toxicity in vivo. We conclude that Nrf2 may underlie a feedback system limiting oxidative load during chronic metabolic stress.
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“Additionally, the Nrf2 activator tertbutylhydroquinone, has attenuated 3-NP toxicity in Nrf2+/+ mice, but not in Nrf2−/− mice185.”
From Mitochondrial Approaches for Neuroprotection (2008) · cites this paper as [185]
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“In the Nrf2 knockout (Nrf2−/−) mice, injection of the mitochondrial complex-II inhibitor 3-NP causes increased motor deficits and striatal lesions as compared to the Nrf2+/+ mice, and these toxic effects of 3-NP were protected by adenoviral mediated over expression of Nrf2185.”
From Mitochondrial Approaches for Neuroprotection (2008) · cites this paper as [185]
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Kensler, T. W., Wakabayashi, N., & Biswal, S. (2007) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.46.120604.141046 · Cited by 3,630
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Metadata
- Authors
- Shih, A. Y., Imbeault, S., Barakauskas, V., Erb, H., Jiang, L., Li, P., & Murphy, T. H.
- Affiliations
- University of British Columbia (CA)
- Corresponding author
- Murphy, Timothy H.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2005-06
- Volume
- 280
- Issue
- 24
- Pages
- 22925-22936
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2028243150
- Cited by
- 273
- References
- 80
- Citations by year
- 2026: 7 · 2025: 4 · 2024: 9 · 2023: 3 · 2022: 4 · 2021: 10 · 2020: 8 · 2019: 7 · 2018: 17 · 2017: 11 · 2016: 16 · 2015: 13 · 2014: 12 · 2013: 17 · 2012: 26
- FWCI
- 5.61
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Heart and Stroke Foundation of Canada
- University of Ottawa
- Rick Hansen Institute
- Canadian Stroke Network
- Michael Smith Health Research BC
- University of British Columbia
- Canadian Institutes of Health Research
- Natural Sciences and Engineering Research Council of Canada
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Receptors and Signaling
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Keywords
- Nrf2, antioxidant response element, neuroprotection, mitochondrial complex II inhibition, 3-nitropropionic acid, succinate dehydrogenase, striatal lesions, motor impairment, tert-butylhydroquinone, Nrf2 inducers, oxidative stress, astrocytes, adenoviral overexpression, Nrf2 knockout mice, metabolic stress
- MeSH terms
- Adenoviridae, Alkaline Phosphatase, Animals, Antioxidants, Astrocytes, Behavior, Animal, Brain, DNA-Binding Proteins, Dose-Response Relationship, Drug, Female, Genotype, Glutathione, Hydroquinones, Immunohistochemistry, Male, Mice, Transgenic, Mitochondria, Neuroglia, Neurons, Nitro Compounds, Placenta, Plasmids, Propionates, Succinate Dehydrogenase, Time Factors, Transfection, Blotting, Western, Trans-Activators, Up-Regulation, Rats, Wistar, DNA Primers, Oxidative Stress, COS Cells, Dietary Supplements, Reverse Transcriptase Polymerase Chain Reaction, Green Fluorescent Proteins, NF-E2-Related Factor 2, Mice, Rats
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