Isotropic Reinforcement to Minimize Nigrostriatal Degeneration

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150万美国人，每年有5万新病例。目前，治疗方法可以缓解症状，但没有改善疾病的治疗干预存在。三十多年来的研究表明，氧化应激参与PD的发病机制和α -突触核蛋白（a-syn）病理的发展。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）。有毒的4-HNE形成的过程开始于多不饱和脂肪酸（PUFA）的氧化。然而，用氘取代氢稳定了多聚脂肪酸的氧化位点，并将反应速度降低了80倍。这种同位素动力学效应减少了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在一定程度上可以通过D-PUFA治疗减轻。我们假设PUFA的同位素增强可以预防和/或减缓PD和α -突触核蛋白病模型的变性进展。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。

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.