Development of novel Amadorins for Diabetic Peripheral Neuropathy

项目总结 阿尔茨海默病(AD)的特点是进行性认知功能障碍和广泛的神经元 淀粉样蛋白b斑块的丢失、积聚和过度磷酸化的tau聚集到神经纤维中 唐格斯。人们对使用抗氧化剂治疗AD和其他疾病有广泛的兴趣 神经退行性病变。正常大脑充满了葡萄糖和抗坏血酸，这两种物质都是 氧化还原金属离子作用下晚期糖基化终末产物(AGE)的来源 催化剂。AGE水平和羧甲基赖氨酸(一种主要的年龄修饰)在 阿尔茨海默病患者大脑。在斑块和斑块中都发现了AGEs修饰和交联蛋白和AGEs 错综复杂的AD大脑。事实上，糖基化有可能对两者的形成起到推动作用。 斑块和缠结。此外，AGEs还会通过产生活性氧来引起毒性作用。 通过与AD大脑中增加的AGE受体(RAGE)相互作用。预防衰老 因此，形成是治疗阿尔茨海默病的合理方法。 越来越多的人认识到，在神经退行性变的过程中 AD和糖尿病，年龄形成是一个可疑的共同致病因素。在我们目前的阶段 我们正在全面测试我们的先导化合物的体内疗效，这是一种专有的非典型药物 抑制氧化还原金属离子催化氧化的抗氧化剂，抗糖尿病周围神经病变 使用1型和2型糖尿病的啮齿动物模型。在本补充材料中，我们将使用两种不同的动物 以探索我们先导化合物的治疗潜力。此应用程序提供了一个 有利和协同的机会，将我们最有效的铅化合物的研究扩展到 非糖尿病AD模型。

PROJECT SUMMARY Alzheimer’s disease (AD) is characterized by progressive cognitive dysfunction and widespread neuronal loss, accumulation of amyloid b plaques and aggregation of hyperphosphorylated tau into neurofribrillary tangles. There has been extensive interest in the use of antioxidants to treat AD and other neurodegenerative pathologies. Normal brains are replete with glucose and ascorbate, both of which are sources of advanced glycation end-products (AGE) via autooxidation in the presence of redox metal-ion catalysts. AGE levels and carboxymethyl lysine, a predominant AGE modification, are increased in the brain of AD patients. AGEs modify and crosslink proteins and AGEs were identified in both plaques and tangles of AD brains. Indeed, glycation has the potential to be a driving influence in formation of both plaques and tangles. Furthermore, AGEs induce toxic effects with formation of reactive oxygen species through interaction with AGE receptors (RAGE), which are increased in AD brains. Preventing AGE formation therefore represents a rational approach for the treatment of AD. There is increasing recognition that there are similarities between the progression of neurodegeneration in AD and diabetes with AGE formation being one suspected common causative factor. In our current Phase II grant, we are comprehensively testing the in vivo efficacy of our lead compound, a proprietary atypical antioxidant that inhibits redox metal-ion catalysis of oxidation, against diabetic peripheral neuropathy using rodent models of type 1 and type 2 diabetes. In this supplement, we will use two different animal models of AD to explore the therapeutic potential of our lead compound. This application offers a propitious and synergistic opportunity to extend the investigation of our most potent lead compound to non-diabetic AD models.