Neuroprotective effects of the triterpenoid, CDDO methyl amide, a potent inducer of Nrf2-mediated transcription

Lichuan Yang, Noel Y. Calingasan, Bobby Thomas, Rajnish K. Charturvedi, Mahmoud Kiaei, Elizabeth J. Wille, Karen T. Liby, Charlotte Williams, Darlene Royce, Renee Risingson, Eric S. Musiek, Jason D. Morrow, Michael Sporn, M. Flint Beal

Research output: Contribution to journalArticle

121 Citations (Scopus)

Abstract

The NF-E2-related factor-2 (Nrf2)/antioxidant response element (ARE) signaling pathway regulates phase 2 detoxification genes, including a variety of antioxidative enzymes. We tested neuroprotective effects of the synthetic triterpenoid CDDO-MA, a potent activator of the Nrf2/ARE signaling. CDDO-MA treatment of neuroblastoma SH-SY5Y cells resulted in Nrf2 upregulation and translocation from cytosol to nucleus and subsequent activation of ARE pathway genes. CDDO-MA blocked t-butylhydroperoxide-induced production of reactive oxygen species (ROS) by activation of ARE genes only in wild type, but not Nrf2 knockout mouse embryonic fibroblasts. Oral administration of CDDO-MA resulted in significant protection against MPTP-induced nigrostriatal dopaminergic neurodegeneration, pathological alpha-synuclein accumulation and oxidative damage in mice. Additionally, CDDO-MA treatment in rats produced significant rescue against striatal lesions caused by the neurotoxin 3-NP, and associated increases in the oxidative damage markers malondialdehyde, F2-Isoprostanes, 8-hydroxy-2-deoxyguanosine, 3-nitrotyrosine, and impaired glutathione homeostasis. Our results indicate that the CDDO-MA renders its neuroprotective effects through its potent activation of the Nrf2/ARE pathway, and suggest that triterpenoids may be beneficial for the treatment of neurodegenerative diseases like Parkinson's disease and Huntington's disease.

Original languageEnglish (US)
Article numbere5757
JournalPloS one
Volume4
Issue number6
DOIs
StatePublished - Jun 1 2009

Fingerprint

NF-E2-Related Factor 2
Antioxidant Response Elements
neuroprotective effect
response elements
Neuroprotective Agents
Transcription
amides
triterpenoids
Amides
transcription (genetics)
antioxidants
Genes
Chemical activation
F2-Isoprostanes
Neurodegenerative diseases
tert-Butylhydroperoxide
Corpus Striatum
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
alpha-Synuclein
Detoxification

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Yang, L., Calingasan, N. Y., Thomas, B., Charturvedi, R. K., Kiaei, M., Wille, E. J., ... Beal, M. F. (2009). Neuroprotective effects of the triterpenoid, CDDO methyl amide, a potent inducer of Nrf2-mediated transcription. PloS one, 4(6), [e5757]. https://doi.org/10.1371/journal.pone.0005757

Neuroprotective effects of the triterpenoid, CDDO methyl amide, a potent inducer of Nrf2-mediated transcription. / Yang, Lichuan; Calingasan, Noel Y.; Thomas, Bobby; Charturvedi, Rajnish K.; Kiaei, Mahmoud; Wille, Elizabeth J.; Liby, Karen T.; Williams, Charlotte; Royce, Darlene; Risingson, Renee; Musiek, Eric S.; Morrow, Jason D.; Sporn, Michael; Beal, M. Flint.

In: PloS one, Vol. 4, No. 6, e5757, 01.06.2009.

Research output: Contribution to journalArticle

Yang, L, Calingasan, NY, Thomas, B, Charturvedi, RK, Kiaei, M, Wille, EJ, Liby, KT, Williams, C, Royce, D, Risingson, R, Musiek, ES, Morrow, JD, Sporn, M & Beal, MF 2009, 'Neuroprotective effects of the triterpenoid, CDDO methyl amide, a potent inducer of Nrf2-mediated transcription', PloS one, vol. 4, no. 6, e5757. https://doi.org/10.1371/journal.pone.0005757
Yang, Lichuan ; Calingasan, Noel Y. ; Thomas, Bobby ; Charturvedi, Rajnish K. ; Kiaei, Mahmoud ; Wille, Elizabeth J. ; Liby, Karen T. ; Williams, Charlotte ; Royce, Darlene ; Risingson, Renee ; Musiek, Eric S. ; Morrow, Jason D. ; Sporn, Michael ; Beal, M. Flint. / Neuroprotective effects of the triterpenoid, CDDO methyl amide, a potent inducer of Nrf2-mediated transcription. In: PloS one. 2009 ; Vol. 4, No. 6.
@article{86c48d772dd646f09888b1fdbc1fe793,
title = "Neuroprotective effects of the triterpenoid, CDDO methyl amide, a potent inducer of Nrf2-mediated transcription",
abstract = "The NF-E2-related factor-2 (Nrf2)/antioxidant response element (ARE) signaling pathway regulates phase 2 detoxification genes, including a variety of antioxidative enzymes. We tested neuroprotective effects of the synthetic triterpenoid CDDO-MA, a potent activator of the Nrf2/ARE signaling. CDDO-MA treatment of neuroblastoma SH-SY5Y cells resulted in Nrf2 upregulation and translocation from cytosol to nucleus and subsequent activation of ARE pathway genes. CDDO-MA blocked t-butylhydroperoxide-induced production of reactive oxygen species (ROS) by activation of ARE genes only in wild type, but not Nrf2 knockout mouse embryonic fibroblasts. Oral administration of CDDO-MA resulted in significant protection against MPTP-induced nigrostriatal dopaminergic neurodegeneration, pathological alpha-synuclein accumulation and oxidative damage in mice. Additionally, CDDO-MA treatment in rats produced significant rescue against striatal lesions caused by the neurotoxin 3-NP, and associated increases in the oxidative damage markers malondialdehyde, F2-Isoprostanes, 8-hydroxy-2-deoxyguanosine, 3-nitrotyrosine, and impaired glutathione homeostasis. Our results indicate that the CDDO-MA renders its neuroprotective effects through its potent activation of the Nrf2/ARE pathway, and suggest that triterpenoids may be beneficial for the treatment of neurodegenerative diseases like Parkinson's disease and Huntington's disease.",
author = "Lichuan Yang and Calingasan, {Noel Y.} and Bobby Thomas and Charturvedi, {Rajnish K.} and Mahmoud Kiaei and Wille, {Elizabeth J.} and Liby, {Karen T.} and Charlotte Williams and Darlene Royce and Renee Risingson and Musiek, {Eric S.} and Morrow, {Jason D.} and Michael Sporn and Beal, {M. Flint}",
year = "2009",
month = "6",
day = "1",
doi = "10.1371/journal.pone.0005757",
language = "English (US)",
volume = "4",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "6",

}

TY - JOUR

T1 - Neuroprotective effects of the triterpenoid, CDDO methyl amide, a potent inducer of Nrf2-mediated transcription

AU - Yang, Lichuan

AU - Calingasan, Noel Y.

AU - Thomas, Bobby

AU - Charturvedi, Rajnish K.

AU - Kiaei, Mahmoud

AU - Wille, Elizabeth J.

AU - Liby, Karen T.

AU - Williams, Charlotte

AU - Royce, Darlene

AU - Risingson, Renee

AU - Musiek, Eric S.

AU - Morrow, Jason D.

AU - Sporn, Michael

AU - Beal, M. Flint

PY - 2009/6/1

Y1 - 2009/6/1

N2 - The NF-E2-related factor-2 (Nrf2)/antioxidant response element (ARE) signaling pathway regulates phase 2 detoxification genes, including a variety of antioxidative enzymes. We tested neuroprotective effects of the synthetic triterpenoid CDDO-MA, a potent activator of the Nrf2/ARE signaling. CDDO-MA treatment of neuroblastoma SH-SY5Y cells resulted in Nrf2 upregulation and translocation from cytosol to nucleus and subsequent activation of ARE pathway genes. CDDO-MA blocked t-butylhydroperoxide-induced production of reactive oxygen species (ROS) by activation of ARE genes only in wild type, but not Nrf2 knockout mouse embryonic fibroblasts. Oral administration of CDDO-MA resulted in significant protection against MPTP-induced nigrostriatal dopaminergic neurodegeneration, pathological alpha-synuclein accumulation and oxidative damage in mice. Additionally, CDDO-MA treatment in rats produced significant rescue against striatal lesions caused by the neurotoxin 3-NP, and associated increases in the oxidative damage markers malondialdehyde, F2-Isoprostanes, 8-hydroxy-2-deoxyguanosine, 3-nitrotyrosine, and impaired glutathione homeostasis. Our results indicate that the CDDO-MA renders its neuroprotective effects through its potent activation of the Nrf2/ARE pathway, and suggest that triterpenoids may be beneficial for the treatment of neurodegenerative diseases like Parkinson's disease and Huntington's disease.

AB - The NF-E2-related factor-2 (Nrf2)/antioxidant response element (ARE) signaling pathway regulates phase 2 detoxification genes, including a variety of antioxidative enzymes. We tested neuroprotective effects of the synthetic triterpenoid CDDO-MA, a potent activator of the Nrf2/ARE signaling. CDDO-MA treatment of neuroblastoma SH-SY5Y cells resulted in Nrf2 upregulation and translocation from cytosol to nucleus and subsequent activation of ARE pathway genes. CDDO-MA blocked t-butylhydroperoxide-induced production of reactive oxygen species (ROS) by activation of ARE genes only in wild type, but not Nrf2 knockout mouse embryonic fibroblasts. Oral administration of CDDO-MA resulted in significant protection against MPTP-induced nigrostriatal dopaminergic neurodegeneration, pathological alpha-synuclein accumulation and oxidative damage in mice. Additionally, CDDO-MA treatment in rats produced significant rescue against striatal lesions caused by the neurotoxin 3-NP, and associated increases in the oxidative damage markers malondialdehyde, F2-Isoprostanes, 8-hydroxy-2-deoxyguanosine, 3-nitrotyrosine, and impaired glutathione homeostasis. Our results indicate that the CDDO-MA renders its neuroprotective effects through its potent activation of the Nrf2/ARE pathway, and suggest that triterpenoids may be beneficial for the treatment of neurodegenerative diseases like Parkinson's disease and Huntington's disease.

UR - http://www.scopus.com/inward/record.url?scp=66749132810&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=66749132810&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0005757

DO - 10.1371/journal.pone.0005757

M3 - Article

C2 - 19484125

AN - SCOPUS:66749132810

VL - 4

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 6

M1 - e5757

ER -