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Cited by 273Genomics, phytochemicals, and oxidative stressNuclear Receptors and SignalingParkinson's Disease Mechanisms and Treatments

Induction of the Nrf2-driven Antioxidant Response Confers Neuroprotection during Mitochondrial Stress in Vivo

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Shih, Andy Y., Imbeault, Sophie, Barakauskas, Vilte, Erb, Heidi, Jiang, Lei, Li, Ping, Murphy, Timothy H.·2005·Journal of Biological Chemistry
DOI 10.1074/jbc.m414635200
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Abstract

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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  • Nrf2 activator tert-butylhydroquinone has attenuated 3-NP toxicity in Nrf2+/+ mice, but not in Nrf2−/− mice.

    “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]

  • In Nrf2 knockout mice, injection of 3-NP causes increased motor deficits and striatal lesions as compared to Nrf2+/+ mice, and these toxic effects of 3-NP were protected by adenoviral mediated over expression of Nrf2.

    “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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Research works printed but not linked: 15

  1. Kang, M. I., Kobayashi, A., Wakabayashi, N., Kim, S. G., and Yamamoto, M. (2004) Proc. Natl. Acad. Sci. U. S. A. 101, 2046 -2051
  2. Wakabayashi, N., Dinkova-Kostova, A. T., Holtzclaw, W. D., Kang, M. I., Kobayashi, A., Yamamoto, M., Kensler, T. W., and Talalay, P. (2004) Proc. Natl. Acad. Sci. U. S. A. 101, 2040 -2045
  3. Dinkova-Kostova, A. T., Holtzclaw, W. D., Cole, R. N., Itoh, K., Wakabayashi, N., Katoh, Y., Yamamoto, M., and Talalay, P. (2002) Proc. Natl. Acad. Sci.
  4. Chan, K., Han, X. D., and Kan, Y. W. (2001) Proc. Natl. Acad. Sci. U. S. A. 98, 4611-4616
  5. Chan, K., and Kan, Y. W. (1999) Proc. Natl. Acad. Sci. U. S. A. 96, 12731-12736
  6. Fahey, J. W., Haristoy, X., Dolan, P. M., Kensler, T. W., Scholtus, I., Stephen- son, K. K., Talalay, P., and Lozniewski, A. (2002) Proc. Natl. Acad. Sci.
  7. Ramos-Gomez, M. C., Kwak, M. K., Dolan, P. M., Itoh, K., Yamamoto, M., Talalay, P., and Kensler, T. W. (2001) Proc. Natl. Acad. Sci. U. S. A. 98, 3410 -3415
  8. Chan, K., Lu, R., Chang, J. C., and Kan, Y. W. (1996) Proc. Natl. Acad. Sci.
  9. Benson, A. M., Hunkeler, M. J., and Talalay, P. (1980) Proc. Natl. Acad. Sci.
  10. Henthorn, P., Zervos, P., Raducha, M., Harris, H., and Kadesch, T. (1988) Proc. Natl. Acad. Sci. U. S. A. 85, 6342-6346
  11. Talalay, P., and Zhang, Y. (1996) Biochem. Soc. Trans. 24, 806 -810
  12. Wu, L., Ashraf, M. H., Facci, M., Wang, R., Paterson, P. G., Ferrie, A., and Juurlink, B. H. (2004) Proc. Natl. Acad. Sci. U. S. A. 101, 7094 -7099
  13. Hayes, J. D., Chanas, S. A., Henderson, C. J., McMahon, M., Sun, C., Moffat, G. J., Wolf, C. R., and Yamamoto, M. (2000) Biochem. Soc. Trans. 28, 33-41
  14. Calkins, M. J., Jakel, R. J., Johnson, D. A., Chan, K., Kan, Y. W., and Johnson, J. A. (2005) Proc. Natl. Acad. Sci. U. S. A. 102, 244 -249
  15. Fahey, J. W., Zhang, Y., and Talalay, P. (1997) Proc. Natl. Acad. Sci. U. S. A. 94, 10367-10372

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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.
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2005-06
Volume
280
Issue
24
Pages
22925-22936
ISSN
0021-9258 (ISSN-L)
DOI
10.1074/jbc.m414635200
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
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 › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
  • Health Sciences › Medicine › 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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