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

Nrf2/ARE 通路激活剂作为帕金森病的治疗靶点

• 批准号: 7849535
• 负责人: Bobby Thomas
• 金额: $ 23.24万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2011-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7849535
• 关键词: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 1-Methyl-4-phenylpyridinium; 3,4-Dihydroxyphenylacetic Acid; 8-hydroxy-2' -deoxyguanosine; Abbreviations; Acids; Acute; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Attenuated; Autopsy; Binding; Biological Availability; Brain; Cell Nucleus; Cessation of life; Chronic; Corpus striatum structure; Cysteine; Dependovirus; Development; Disease; Dopamine; Drug Delivery Systems; Drug Metabolic Detoxication; Drug usage; Enzymes; Event; Experimental Animal Model; Experimental Models; Genes; Genetic Programming; Genetic Transcription; Glial Fibrillary Acidic Protein; Glutamate-Cysteine Ligase; Glutathione S-Transferase; Goals; Homovanillic Acid; Human; ITGAM gene; Impairment; Inflammation; Inflammatory; Inhibitory Concentration 50; Intoxication; Ions; Knockout Mice; Leucine Zippers; Lewy Body Disease; Measures; Messenger RNA; Modeling; Movement Disorders; Mus; NAD(P)H dehydrogenase (quinone) 1, human; NADP; NF-E2-related factor 2; NF-kappa B; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neurons; Neurotoxins; Nuclear; Oral Administration; Oxidative Stress; Parkinson Disease; Parkinsonian Disorders; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Phase; Play; Proteins; Reduced Glutathione; Relative (related person); Response Elements; Reverse Transcriptase Polymerase Chain Reaction; Rodent Model; Role; Secondary Parkinson Disease; Signal Pathway; Signal Transduction; Substantia nigra structure; System; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Toxic effect; Transcription Factor AP-1; Transgenes; Treatment Efficacy; Tyrosine 3-Monooxygenase; Ubiquitin; United States; cyclooxygenase 2; dopaminergic neuron; drug candidate; heme oxygenase-1; human NOS2A protein; in vivo; macrophage; mitochondrial dysfunction; mouse model; mutant; neuroinflammation; neuroprotection; neurotoxicity; overexpression; oxidation; oxidative damage; pars compacta; prevent; public health relevance; response; selective expression; synuclein; therapeutic target; transcription factor

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.

描述(申请人提供)：帕金森病(PD)是一种毁灭性的神经退行性运动障碍，其特征是黑质中含有多巴胺的神经元丢失，目前在美国约有150万人受到影响。虽然帕金森病的病因尚不清楚，但氧化损伤和炎症在帕金森病的发病机制中起着关键作用，因为Nrf2/ARE(核因子-E2相关因子2/抗氧化反应元件)信号的受损似乎触发了一条不可逆转的途径，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条非常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Are驱动的一系列细胞保护基因的关键调节因子，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，在大脑中实现了更高的生物利用度，并且是Nrf2/ARE途径的有效激活剂，它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激动剂减轻帕金森神经毒素MPTP(1-methyl-4-phenyl-1，2，3，6-tetrahydropyridine).引起的多巴胺能神经变性我们推测，这些合成的三萜类化合物在预防帕金森病患者的多巴胺能神经变性方面具有巨大的潜在治疗潜力。为了检验这一假说，本文提出了两个具体目标。目的1检测激活Nrf2/ARE通路的三萜类药物CDDO(2-氰基-3，12-二氧代-1，9-二烯-28-OIC酸)甲胺、乙胺和三氟乙胺在急性和慢性MPTP帕金森病小鼠模型中发挥神经保护作用的相对有效性，并利用野生型和NRF2基因敲除小鼠检测这些三萜类药物调节的Nrf2/ARE信号转导，以努力确定它们确切的神经保护模式。目的2通过在黑质多巴胺能神经元中选择性表达突变型人A53T 1-突触核蛋白诱导的帕金森病，研究这些三萜类药物选择性表达Nrf2/ARE信号转导通路阻断突变型人A53T 1-突触核蛋白诱导的帕金森病的疗效。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，检测这些三萜类化合物上调抗氧化基因和下调炎症基因的神经保护作用，将使我们能够将这些化合物开发成潜在的治疗药物，阻断帕金森病中多巴胺能神经元的死亡。 公共卫生相关性：这项研究建议使用MPTP和1-突触核蛋白帕金森病(PD)小鼠模型来检验激活神经保护性Nrf2/ARE信号通路的合成三萜类化合物在抢救多巴胺能神经变性方面的相对有效性。这项研究将使我们能够确定最好的三萜类化合物及其作用机制，可以作为治疗帕金森病的潜在候选药物。