Antioxidant Approaches to Alzheimer's Disease Therapy

描述（由申请人提供）：越来越多的证据表明，氧化损伤可能有助于神经退行性疾病的发病机制，如阿尔茨海默病（AD）。最近的一些研究表明，氧化损伤可能先于β -淀粉样蛋白的沉积，并与之有因果关系。相反，β -淀粉样蛋白可能引起氧化损伤。氧化剂和生物系统主要有两大类；活性氧中间体和活性氮中间体。许多研究表明，通过氧化损伤标志物评估，阿尔茨海默病死后脑组织中活性氧中间体增加。根据3-硝基酪氨酸的生化和免疫细胞化学测量，活性氮中间体似乎也有所增加。我们的数据已经被其他人证实，表明在阿尔茨海默病死后脑组织和转基因小鼠模型中，神经元内的诱导型一氧化氮合酶（NOS2）免疫反应性增加。在AD转基因小鼠模型中，基因降低NOS2活性可显著减少β -淀粉样蛋白沉积。本应用的目标是利用两种化合物，它们可以阻断活性氧和活性氮中间体。我们将利用辅酶Q10和l-亚氨基乙基-l -赖氨酸（L-NIL）在转基因AD小鼠模型中应用。辅酶q10是电子传递基因的辅助因子，具有较强的抗氧化性能。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治疗是否可以对β -淀粉样蛋白沉积和氧化损伤发挥神经保护作用，并改善AD转基因小鼠模型的记忆。如果我们能够证明辅酶q10和L-NIL的显著作用，这可能会导致减缓AD进展的新疗法的快速发展。

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.