The DOI matches its Crossref record; 8 of the 8 references it cites were found in a registry or an index.
Targeting Nrf2-Mediated Gene Transcription by Extremely Potent Synthetic Triterpenoids Attenuate Dopaminergic Neurotoxicity in the MPTP Mouse Model of Parkinson's Disease
Open accessAbstract
UNLABELLED: Although the etiology of Parkinson's disease (PD) remains unclear, ample empirical evidence suggests that oxidative stress is a major player in the development of PD and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity. Nuclear factor E2-related factor 2 (Nrf2) is a redox-sensitive transcription factor that upregulates a battery of antioxidant response element (ARE)-driven antioxidative and cytoprotective genes that defend against oxidative stress. AIMS: We evaluated whether the strategy of activation of Nrf2 and its downstream network of cytoprotective genes with small molecule synthetic triterpenoids (TP) attenuate MPTP-induced PD in mice. RESULTS: We show that synthetic TP are thus far the most potent and direct activators of the Nrf2 pathway using a novel Neh2-luciferase reporter. They upregulate several cytoprotective genes, including those involved in glutathione biosynthesis in vitro. Oral administration of TP that were structurally modified to penetrate the brain-induced messenger RNA and protein levels for a battery of Nrf2-dependent cytoprotective genes reduced MPTP-induced oxidative stress and inflammation, and ameliorated dopaminergic neurotoxicity in mice. The neuroprotective effect of these TP against MPTP neurotoxicity was dependent on Nrf2, since treatment with TP in Nrf2 knockout mice failed to block against MPTP neurotoxicity and induce Nrf2-dependent cytoprotective genes. INNOVATION: Extremely potent synthetic TP that are direct activators of the Nrf2 pathway block dopaminergic neurodegeneration in the MPTP mouse model of PD. CONCLUSION: Our results indicate that activation of Nrf2/antioxidant response element (ARE) signaling by synthetic TP is directly associated with their neuroprotective effects against MPTP neurotoxicity and suggest that targeting the Nrf2/ARE pathway is a promising approach for therapeutic intervention in PD.
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Cites
Mitochondrial Dysfunction and Oxidative Stress in Neurodegenerative Diseases
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Stress-activated cap’n’collar transcription factors in aging and human disease
Sykiotis, G. P., & Bohmann, D. (2010) · Science Signaling · doi:10.1126/scisignal.3112re3 · Cited by 776 · cited 2×
“The capacity to induce an Nrf2-mediated cytoprotective response declines with age, which is the main risk factor for PD (37).”
BackgroundTriterpenoids and rexinoids as multifunctional agents for the prevention and treatment of cancer
Liby, K. T., Yore, M. M., & Sporn, M. B. (2007) · Nature Reviews Cancer · doi:10.1038/nrc2129 · Cited by 637 · cited 2×
“Synthetic triterpenoids (TP) such as 2-cyano-3-,12-dioxooleana-1,9 (11)-dien-28-oic acid (CDDO) and its derivatives are potent activators of the Nrf2/ARE pathway (8, 22, 23, 49).”
BackgroundSelf-citationCaspase signalling controls microglia activation and neurotoxicity
Burguillos, M. A., Deierborg, T., Kavanagh, E., Persson, A., Hajji, N., Garcia-Quintanilla, A., Cano, J., Brundin, P., Englund, E., Venero, J. L., et al. (2011) · Nature · doi:10.1038/nature09788 · Cited by 585
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Cited by
The KEAP1-NRF2 system: a thiol-based sensor-effector apparatus for maintaining redox homeostasis
Yamamoto, M., Kensler, T. W., & Motohashi, H. (2018) · Physiological Reviews · doi:10.1152/physrev.00023.2017 · Cited by 1,968
Self-citationThe emerging role of Nrf2 in mitochondrial function
Dinkova-Kostova, A. T., & Abramov, A. Y. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.04.036 · Cited by 983
Tebay, L. E., Robertson, H., Durant, S. T., Vitale, S. R., Penning, T. M., Dinkova-Kostova, A. T., & Hayes, J. D. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.06.021 · Cited by 837
Buendia, I., Michalska, P., Navarro, E., Gameiro, I., Egea, J., & León, R. (2016) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2015.11.003 · Cited by 678
Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach
Cuadrado, A., Manda, G., Hassan, A., Alcaraz, M. J., Barbas, C., Daiber, A., Ghezzi, P., León, R., López, M. G., Oliva, B., et al. (2018) · Pharmacological Reviews · doi:10.1124/pr.117.014753 · Cited by 632
Metadata
- Authors
- Kaidery, N. A., Banerjee, R., Yang, L., Smirnova, N. A., Hushpulian, D. M., Liby, K. T., Williams, C. R., Yamamoto, M., Kensler, T. W., Ratan, R. R., Sporn, M. B., Beal, M. F., Gazaryan, I. G., & Thomas, B.
- Venue
- Antioxidants & Redox Signaling
- Publisher
- SAGE Publications
- Published
- 2013-01-10
- Volume
- 18
- Issue
- 2
- Pages
- 139-157
- ISSN
- 1523-0864 (ISSN-L)
- 1557-7716
- OpenAlex
- W2038809517
- Cited by
- 170
- References
- 8
- FWCI
- 10.47
- Type
- journal article
- Language
- en
- Open access
- green
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- Kaidery, N. A., Banerjee, R., Yang, L., Smirnova, N. A., Hushpulian, D. M., Liby, K. T., Williams, C. R., Yamamoto, M., Kensler, T. W., Ratan, R. R., Sporn, M. B., Beal, M. F., Gazaryan, I. G., & Thomas, B. (2013). Targeting Nrf2-Mediated Gene Transcription by Extremely Potent Synthetic Triterpenoids Attenuate Dopaminergic Neurotoxicity in the MPTP Mouse Model of Parkinson's Disease. Antioxidants & Redox Signaling. https://doi.org/10.1089/ars.2011.4491
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