title: Targeting Nrf2-mediated gene transcription by extremely potent synthetic triterpenoids attenuate dopaminergic neurotoxicity in the MPTP mouse model of Parkinson's disease.
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.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  Extremely potent synthetic TP that are direct activators of the Nrf2 pathway block dopaminergic neurodegeneration in the MPTP mouse model of PD.
  
  
  CONCLUSIONS
  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.
authors: Department of Pharmacology & Toxicology, Georgia Health Sciences University, Augusta, GA 30912, USA.
authors: Navneet Ammal
authors: NA
authors: Kaidery
authors: Rebecca
authors: R
authors: Banerjee
authors: Lichuan
authors: L
authors: Yang
authors: Natalya A
authors: NA
authors: Smirnova
authors: Dmitry M
authors: DM
authors: Hushpulian
authors: Karen T
authors: KT
authors: Liby
authors: Charlotte R
authors: CR
authors: Williams
authors: Masayuki
authors: M
authors: Yamamoto
authors: Thomas W
authors: TW
authors: Kensler
authors: Rajiv R
authors: RR
authors: Ratan
authors: Michael B
authors: MB
authors: Sporn
authors: M Flint
authors: MF
authors: Beal
authors: Irina G
authors: IG
authors: Gazaryan
authors: Bobby
authors: B
authors: Thomas
mesh_terms: D000284:Administration, Oral; D000818:Animals; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D020267:MPTP Poisoning / Q000150:complications*; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics*; D010300:Parkinson Disease / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects* / Q000502:physiology; D014315:Triterpenes / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D014315:Triterpenes; D004298:Dopamine