Activators of Nrf2/ARE pathway as therapeutic target for Parkinson's Disease

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DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a devastating neurodegenerative movement disorder characterized by a loss of dopamine-containing neurons of substantia nigra, which currently affects about 1.5 million people in the United States. While the causes of PD are unknown, a critical role of oxidative damage and inflammation has been implicated in PD pathogenesis, in that impairment of Nrf2/ARE (NF-E2 related factor 2/antioxidant response element) signaling seems to trigger an irreversible pathway causing oxidative damage, mitochondrial dysfunction and neuroinflammation leading to neurodegeneration. An extremely promising pathway for neurotherapeutics in neurodegenerative diseases is the Nrf2/ARE signaling pathway. The leucine-zipper transcription factor Nrf2 has been identified as a key regulatory factor in the coordinated induction of ARE driven battery of cytoprotective genes, including those encoding for a variety of both antioxidant and anti-inflammatory proteins. We have developed synthetic triterpenoids that are structurally modified to achieve increased bioavailability in the brain and are potent activators of Nrf2/ARE pathway which upregulate large number of genes involved in antioxidant defenses and downregulate genes involved in inflammation. Oral administration of these Nrf2/ARE activators attenuate dopaminergic neurodegeneration caused by parkinsonian neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). We hypothesize that these synthetic triterpenoids possess great potential as therapeutic candidates in preventing dopaminergic neurodegeneration in PD. Two specific aims are proposed to test the hypothesis. Aim 1 will examine the relative efficacy of triterpenoid drugs CDDO (2-cyano-3, 12-dioxooleana-1,9-dien-28- oic acid) methylamide, ethylamide, and trifluoroethylamide that activates the Nrf2/ARE pathway, in exerting neuroprotective effects in both acute and chronic MPTP mouse models of PD and will also determine the Nrf2/ARE signaling modulated by these triterpenoid drugs using wild type and Nrf2 knockout mice in an effort to identify their precise mode of neuroprotection. Aim 2 will examine the therapeutic efficacy and Nrf2/ARE signaling as the mode of action of these triterpenoid drugs in blocking mutant human A53T 1-synuclein-induced PD by selectively expressing this transgene in nigral dopaminergic neurons. Testing neuroprotective efficacy of these triterpenoids that upregulate antioxidant genes and downregulate inflammatory genes by activating Nrf2/ARE pathway in the MPTP and 1-synuclein-induced rodent models of PD will enable us to develop these compounds into potential therapeutic drugs to block the death of dopaminergic neurons in Parkinson's disease. PUBLIC HEALTH RELEVANCE: This study proposes to examine the relative efficacy of synthetic triterpenoids that activate the neuroprotective Nrf2/ARE signaling pathway in rescuing dopaminergic neurodegeneration using the MPTP and 1-synuclein mouse model of Parkinson's disease (PD). The study will enable us to identify the best triterpenoid and its mechanism of action that could be used as a potential drug candidate for therapeutic intervention in PD.