Targeting nrf2-mediated gene transcription by extremely potent synthetic triterpenoids attenuate dopaminergic neurotoxicity in the MPTP mouse model of parkinson's disease

Navneet Ammal Kaidery, Rebecca Banerjee, Lichuan Yang, Natalya A. Smirnova, Dmitry M. Hushpulian, Karen T. Liby, Charlotte R. Williams, Masayuki Yamamoto, Thomas W. Kensler, Rajiv R. Ratan, Michael B. Sporn, M. Flint Beal, Irina G. Gazaryan, Bobby Thomas

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)139-157
Number of pages19
JournalAntioxidants and Redox Signaling
Volume18
Issue number2
DOIs
StatePublished - Jan 10 2013

Fingerprint

NF-E2-Related Factor 2
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Transcription
Parkinson Disease
Genes
Antioxidant Response Elements
Oxidative stress
Oxidative Stress
Neuroprotective Agents
Up-Regulation
Chemical activation
Gene Regulatory Networks
Biosynthesis
Luciferases
Knockout Mice
Oxidation-Reduction
Glutathione
Oral Administration
Brain
Transcription Factors

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

Cite this

Targeting nrf2-mediated gene transcription by extremely potent synthetic triterpenoids attenuate dopaminergic neurotoxicity in the MPTP mouse model of parkinson's disease. / Kaidery, Navneet Ammal; Banerjee, Rebecca; Yang, Lichuan; Smirnova, Natalya A.; Hushpulian, Dmitry M.; Liby, Karen T.; Williams, Charlotte R.; Yamamoto, Masayuki; Kensler, Thomas W.; Ratan, Rajiv R.; Sporn, Michael B.; Beal, M. Flint; Gazaryan, Irina G.; Thomas, Bobby.

In: Antioxidants and Redox Signaling, Vol. 18, No. 2, 10.01.2013, p. 139-157.

Research output: Contribution to journalArticle

Kaidery, NA, Banerjee, R, Yang, L, Smirnova, NA, Hushpulian, DM, Liby, KT, Williams, CR, Yamamoto, M, Kensler, TW, Ratan, RR, Sporn, MB, Beal, MF, Gazaryan, IG & 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 and Redox Signaling, vol. 18, no. 2, pp. 139-157. https://doi.org/10.1089/ars.2011.4491
Kaidery, Navneet Ammal ; Banerjee, Rebecca ; Yang, Lichuan ; Smirnova, Natalya A. ; Hushpulian, Dmitry M. ; Liby, Karen T. ; Williams, Charlotte R. ; Yamamoto, Masayuki ; Kensler, Thomas W. ; Ratan, Rajiv R. ; Sporn, Michael B. ; Beal, M. Flint ; Gazaryan, Irina G. ; Thomas, Bobby. / Targeting nrf2-mediated gene transcription by extremely potent synthetic triterpenoids attenuate dopaminergic neurotoxicity in the MPTP mouse model of parkinson's disease. In: Antioxidants and Redox Signaling. 2013 ; Vol. 18, No. 2. pp. 139-157.
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AU - Smirnova, Natalya A.

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