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. Aims: We evaluated whether the strategy of activation of Nrf2 and its downstream network of cytoprotective genes with small molecule synthetic triterpenoids (TP) attenuate MPTPinduced 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. Antioxid. Redox Signal. 18, 139-157.

The Neuroprotective Effect of Dimethyl Fumarate in an MPTP-Mouse Model of Parkinson's Disease: Involvement of Reactive Oxygen Species/Nuclear Factor-κB/Nuclear Transcription Factor Related to NF-E2

“…The Nrf-2 signaling cascade is a promising therapeutic pathway via transcriptional modulation of both inflammation and oxidative stress, and it has generated increasing clinical interest in using Nrf-2 activators in inflammatory diseases (32). A number of drugs that activate the Nrf-2 system are already in clinical use, including the fumaric acid ester DMF (57).…”

“…Recently, Nrf-2 activation was observed in humans in settings of chronic diseases such as PD (30,32,37), Alzheimer's disease (14), and amyotrophic lateral sclerosis (52). Brennan et al showed that DMF, by acting as an electrophile, modulates specific KEAP1 cysteine residues and exerts more robust allosteric conformational changes-leading to a diminished KEAP1-dependent degradation of Nrf-2 (10).…”

“…DMF is currently used as an oral therapeutic agent for the treatment of relapsing forms of multiple sclerosis (9,32). DMF exerts anti-inflammatory and cytoprotective effects through activation of the Nrf-2 pathway in neuronal cells (2).…”

Role of the Transcription Factor Nrf2 in Parkinson’s Disease: New Insights

“…The neuroprotective effect of these TP against MPTP neurotoxicity was dependent on NRF2, since treatment with TP in NRF2 knockout mice Diagram of the molecular events triggered by α-synuclein and the protective way of action of DMF through NRF2 activation. DMF through NRF2 is able to modulate protein aggregation (modifying proteasome and autophagy), oxidative stress (increasing the expression of antioxidant enzymes) and neuroinflammation (increasing anti-inflammatory markers and reducing pro-inflammatory cytokines) failed to block against MPTP neurotoxicity and induce NRF2-dependent cytoprotective genes [102].…”

Adverse Outcome Pathway on binding of agonists to ionotropic glutamate receptors in adult brain leading to excitotoxicity that mediates neuronal cell death, contributing to learning and memory impairment

“…Moreover, an impressive number of disease-specific proteins interact with mitochondria. Thus, therapies targeting basic mitochondrial processes, such as energy metabolism or free-radical generation hold some promise (Kaidery et al, 2013).…”