Isotropic Reinforcement to Minimize Nigrostriatal Degeneration

各向同性强化以最大限度地减少黑质纹状体变性

• 批准号: 8448063
• 负责人: Amy Beatrice Manning-Bog
• 金额: $ 21.34万
• 依托单位: SRI INTERNATIONAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8448063
• 关键词: 4 hydroxynonenal; Acids; Affect; American; Antioxidants; Attenuated; Biological; Blood - brain barrier anatomy; Brain; Carbon; Corpus striatum structure; DNA Damage; Data; Deposition; Deuterium; Development; Diet; Dietary intake; Disease; Disease Progression; Disease model; Docosahexaenoic Acids; Dopamine; Dose; Esters; Etiology; Evaluation; Event; Exercise; Fatty Acids; Figs - dietary; Gastrointestinal tract structure; Genetic; Goals; Herbicides; Human; Hydrogen; Hydrogen Peroxide; Injury; Isotopes; Kinetics; Lipid Peroxidation; Mass Spectrum Analysis; Measures; Mediating; Membrane Lipids; Membrane Proteins; Mitochondria; Modeling; Modification; Mus; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neurologic; Neurons; Nutrient; Omega-3 Fatty Acids; Organism; Oxidation-Reduction; Oxidative Phosphorylation; Oxidative Stress; Paraquat; Parkinson Disease; Pathogenesis; Pathology; Pathway interactions; Pharmaceutical Preparations; Polyunsaturated Fatty Acids; Pre-Clinical Model; Process; Production; Proteins; Psychological reinforcement; Reaction; Reactive Oxygen Species; Research; Saline; Site; Source; Symptoms; Testing; Therapeutic; Therapeutic Intervention; Time; Toxic effect; Transgenic Organisms; alpha synuclein; clinical efficacy; dietary requirement; disorder risk; fatty acid metabolism; feeding; improved; insight; mitochondrial dysfunction; mitochondrial membrane; motor deficit; mouse model; mutant; nervous system disorder; neuroprotection; novel strategies; overexpression; oxidation; oxidative damage; pre-clinical; preclinical efficacy; prevent; protective effect; response; success; synucleinopathy; therapeutic target; toxicant

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is one of the most common neurodegenerative diseases, affecting 1,500,000 Americans, with 50,000 new cases each year. Currently, therapies are available to alleviate symptoms, but no disease-modifying therapeutic intervention exists. Over thirty years of research indicate that oxidative stress contributes to pathogenesis in PD and the development of alpha-synuclein (a-syn) pathology. However, studies utilizing anti-oxidants show little efficacy. We propose a novel approach to alleviate oxidative injury by utilizing isotopic reinforcement. Toxic reactive oxygen species (ROS) and downstream reactive carbonyl products (RCP) such as 4-hydroxynonenal (4-HNE), are generated in mitochondria. The process of the toxic 4-HNE formation begins with the oxidation of polyunsaturated fatty acids (PUFA). However, substitution of deuterium for hydrogen stabilizes the site of oxidation in PUFA and slows this reaction by up to 80-fold. This kinetic isotope effect reduces the production of 4-HNE and other toxic RCP. Our preliminary data show that MPTP-induced nigrostriatal damage is at least in part reduced by treatment with D-PUFA in mice. We hypothesize that isotopic reinforcement of PUFA will prevent and/or slow progression of degeneration in models of PD and alpha-synucleinopathy. Importantly, if our hypotheses are correct, the window to an entirely new spectrum of therapeutic targets is opened for neurodegenerative and other disorders characterized by oxidative injury.

描述（由申请人提供）：帕金森病（PD）是最常见的神经退行性疾病之一，影响1，500，000美国人，每年有50，000例新发病例。目前，治疗可用于缓解症状，但不存在改善疾病的治疗干预。三十多年的研究表明，氧化应激有助于PD的发病机制和α-突触核蛋白（α-syn）病理学的发展。然而，使用抗氧化剂的研究显示效果甚微。我们提出了一种新的方法来减轻氧化损伤，利用同位素加固。在线粒体中产生毒性活性氧（ROS）和下游活性羰基产物（RCP），如4-羟基壬烯醛（4-HNE）。有毒4-HNE形成的过程始于多不饱和脂肪酸（PUFA）的氧化。然而，用氘取代氢稳定了PUFA中的氧化位点，并使该反应减慢了80倍。这种动力学同位素效应减少了4-HNE和其他有毒RCP的产生。我们的初步数据表明，MPTP诱导的黑质纹状体损伤至少部分减少了D-PUFA治疗小鼠。我们假设PUFA的同位素强化将预防和/或减缓PD和α-突触核蛋白病模型中的变性进展。重要的是，如果我们的假设是正确的，则为神经退行性疾病和其他以氧化损伤为特征的疾病打开了一个全新的治疗靶点的窗口。