Isotropic Reinforcement to Minimize Nigrostriatal Degeneration

描述(申请人提供)：帕金森病(PD)是最常见的神经退行性疾病之一，影响着1500,000美国人，每年新增50,000例。目前，治疗方法可用于缓解症状，但不存在改变疾病的治疗干预措施。三十多年的研究表明，氧化应激参与了帕金森病的发病机制和α-突触核蛋白(a-syn)的病理发展。然而，使用抗氧化剂的研究表明效果不大。我们提出了一种利用同位素强化来减轻氧化损伤的新方法。线粒体中产生有毒的活性氧物种(ROS)和下游的活性羰基产物(RCP)，如4-羟基壬烯醛(4-HNE)。有毒的4-HNE的形成过程始于多不饱和脂肪酸(PUFA)的氧化。然而，用重氢取代氢可以稳定多不饱和脂肪酸中的氧化位置，并使反应速度减慢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。我们的初步数据显示，D-PUFA治疗至少部分减轻了MPTP引起的小鼠黑质纹状体损伤。我们假设，多不饱和脂肪酸的同位素强化将防止和/或减缓帕金森病和α-突触核病模型的变性进展。重要的是，如果我们的假设是正确的，那么通往全新治疗靶点的窗口就会为神经退行性疾病和其他以氧化损伤为特征的疾病打开。

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.