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

描述（由申请人提供）：帕金森病（PD）是一种破坏性的神经退行性运动障碍，其特征是黑质含多巴胺神经元的丧失，目前在美国约有150万人受到影响。虽然PD的病因尚不清楚，但氧化损伤和炎症在PD的发病机制中起着关键作用，因为Nrf2/ are （NF-E2相关因子2/抗氧化反应元件）信号的损伤似乎触发了一个不可逆的途径，导致氧化损伤、线粒体功能障碍和神经炎症导致神经退行性变。Nrf2/ARE信号通路是神经退行性疾病的一个极有前途的神经治疗途径。亮氨酸拉链转录因子Nrf2已被确定为协调诱导由ARE驱动的细胞保护基因电池的关键调控因子，包括编码各种抗氧化和抗炎蛋白的基因。我们已经开发出合成的三萜类化合物，它们经过结构修饰以提高大脑的生物利用度，并且是Nrf2/ are途径的有效激活剂，该途径上调了大量参与抗氧化防御的基因，下调了参与炎症的基因。口服这些Nrf2/ARE激活剂可减轻帕金森神经毒素MPTP（1-甲基-4-苯基-1,2,3,6-四氢吡啶）引起的多巴胺能神经变性。我们假设这些合成的三萜在预防PD患者多巴胺能神经变性方面具有很大的治疗潜力。为了验证这一假设，提出了两个具体目标。目的1将研究激活Nrf2/ARE通路的三萜类药物CDDO（2-氰- 3,12 -二氧齐烷-1,9-二烯-28-酸）甲酰胺、乙胺和三氟乙胺在急性和慢性MPTP小鼠PD模型中发挥神经保护作用的相对功效，并利用野生型和Nrf2敲除小鼠，确定这些三萜类药物调节的Nrf2/ARE信号，以确定其精确的神经保护模式。目的2将通过在黑质多巴胺能神经元中选择性表达这种转基因，研究这些三萜药物在阻断突变型人a53t1 -突触核蛋白诱导的PD中的治疗效果和Nrf2/ARE信号作为作用模式。在MPTP和1-突触核蛋白诱导的帕金森病啮齿动物模型中，通过激活Nrf2/ARE通路，检测这些上调抗氧化基因和下调炎症基因的三萜的神经保护作用，将使我们能够将这些化合物开发成潜在的治疗药物，以阻断帕金森病多巴胺能神经元的死亡。

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.