Antioxidant Approaches to Alzheimer's Disease Therapy

阿尔茨海默病治疗的抗氧化方法

• 批准号: 7229871
• 负责人: M FLINT BEAL
• 金额: $ 16.92万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-15 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7229871
• 关键词: 3-nitrotyrosine; Alzheimer' s Disease; Amyloid beta-Protein; Amyloid deposition; Amyotrophic Lateral Sclerosis; Antioxidants; Autopsy; Biochemical; Biological; Cerebral cortex; Class; Clinical; Coenzyme Q10; Coenzymes; Data; Deposition; Detection; Development; Diffusion; Electron Transport; Generations; Genes; Genetic; Goals; Grant; High Pressure Liquid Chromatography; Hippocampus (Brain); Huntington Disease; Lead; Link; Mass Spectrum Analysis; Measurement; Measures; Mediating; Memory; Mus; N(6)-(1-iminoethyl)lysine; NOS2A gene; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Nitrogen; Numbers; Oxidants; Oxidative Stress; Parkinson Disease; Pathogenesis; Patients; Peroxonitrite; Personal Satisfaction; Property; Reaction; Reactive Oxygen Species; Source; System; Therapy Clinical Trials; Thinking; Tissues; Transgenic Organisms; Translating; Ventricular; brain tissue; cofactor; drug discovery; human NOS2A protein; human subject; immunocytochemistry; immunoreactivity; improved; inhibitor/antagonist; mild neurocognitive impairment; mouse model; reactive oxygen intermediate; therapy development

DESCRIPTION (provided by applicant): There is increasing evidence that oxidative damage may contribute to the pathogenesis of neurodegenerative diseases such as Alzheimer's Disease (AD). A number of recent studies have suggested that oxidative damage may precede and be causally linked to the deposition of beta-amyloid. Conversely, beta-amyloid may induce oxidative damage. There are two major classes of oxidants and biological systems; reactive oxygen intermediates and reactive nitrogen intermediates. A number of studies have shown that there are increased reactive oxygen intermediates in AD postmortem brain tissue as assessed by oxidative damage markers. There also appears to be increased reactive nitrogen intermediates as assessed by biochemical and immunocytochemical measurements of 3-nitrotyrosine. Our data, which has been confirmed by others, shows that there is an increase in inducible nitric oxide synthase (NOS2) immunoreactivity within neurons in both AD postmortem brain tissue, as well as in transgenic mouse models. Genetic reduction of NOS2 activity markedly reduced beta-amyloid deposition in a transgenic mouse model of AD. The goals of the present application are to utilize two compounds, which can block reactive oxygen species and reactive nitrogen intermediates. We will utilize coenzyme Q10 and L-iminoethyl-L-lysine (L-NIL) in transgenic mouse models of AD. CoQ10 is a cofactor of the electron transport gene, which has strong antioxidant properties. It is extremely well tolerated in human subjects and is under clinical development for treatment of Parkinson's Disease, Huntington's Disease and amyotrophic lateral sclerosis. We will also look at the effects of L-iminoethyl-L-lysine, which is a relatively specific inhibitor of NOS2. We will determine whether treatment with either CoQ10 or L-NIL can exert neuroprotective effects against beta-amyloid deposition and oxidative damage, and improve memory in transgenic mouse models of AD. If we can demonstrate significant effects of CoQ10 and L-NIL, this could lead to rapid development of new therapies for slowing the progression of AD.

描述（由申请人提供）：越来越多的证据表明氧化损伤可能导致神经退行性疾病如阿尔茨海默病（AD）的发病机制。最近的许多研究表明，氧化损伤可能先于β-淀粉样蛋白的沉积发生，并与β-淀粉样蛋白的沉积存在因果关系。相反，β-淀粉样蛋白可能诱发氧化损伤。氧化剂和生物系统有两大类：活性氧中间体和活性氮中间体。许多研究表明，通过氧化损伤标记物评估，AD 死后脑组织中的活性氧中间体增加。通过 3-硝基酪氨酸的生化和免疫细胞化学测量评估，活性氮中间体似乎也有所增加。我们的数据已得到其他人的证实，表明在 AD 死后脑组织以及转基因小鼠模型中，神经元内的诱导型一氧化氮合酶 (NOS2) 免疫反应性有所增加。在 AD 转基因小鼠模型中，NOS2 活性的遗传降低显着减少了 β-淀粉样蛋白沉积。本申请的目标是利用两种可以阻断活性氧和活性氮中间体的化合物。我们将在 AD 转基因小鼠模型中利用辅酶 Q10 和 L-亚氨基乙基-L-赖氨酸 (L-NIL)。 CoQ10是电子传递基因的辅助因子，具有很强的抗氧化特性。它在人类受试者中具有极好的耐受性，目前正在临床开发中，用于治疗帕金森病、亨廷顿病和肌萎缩侧索硬化症。我们还将研究 L-亚氨基乙基-L-赖氨酸的作用，它是一种相对特异性的 NOS2 抑制剂。我们将确定 CoQ10 或 L-NIL 治疗是否可以发挥针对 β-淀粉样蛋白沉积和氧化损伤的神经保护作用，并改善 AD 转基因小鼠模型的记忆力。如果我们能够证明 CoQ10 和 L-NIL 的显着作用，这可能会导致新疗法的快速开发，以减缓 AD 的进展。