Development of novel Amadorins for Diabetic Peripheral Neuropathy

开发治疗糖尿病周围神经病变的新型 Amadorins

• 批准号: 10284641
• 负责人: RAJA G KHALIFAH
• 金额: $ 45.82万
• 依托单位: PRAETEGO, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-19 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10284641
• 关键词: Advanced Glycosylation End Products; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease patient; Animal Model; Animals; Antioxidants; Automobile Driving; Brain; Catalysis; Development; Diabetes Mellitus; Glucose; Grant; Impaired cognition; Insulin-Dependent Diabetes Mellitus; Investigation; Ions; Lead; Lysine; Metals; Modification; Nerve Degeneration; Neurofibrillary Tangles; Non-Insulin-Dependent Diabetes Mellitus; Oxidation-Reduction; Pathology; Peripheral Nervous System Diseases; Phase; Reactive Oxygen Species; Rodent Model; Senile Plaques; Source; Therapeutic; Toxic effect; ascorbate; autooxidation; catalyst; diabetic; glycation; hyperphosphorylated tau; in vivo evaluation; inhibitor/antagonist; interest; neuron loss; non-diabetic; novel; oxidation; prevent; protein crosslink; receptor for advanced glycation endproducts

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.

项目摘要 阿尔茨海默病（Alzheimer's disease，AD）是一种以进行性认知功能障碍和广泛的神经元损害为特征的疾病， 淀粉样蛋白B斑的损失、积累和过度磷酸化的tau聚集成神经纤维 缠结。人们对使用抗氧化剂治疗AD和其他疾病产生了广泛的兴趣。 神经退行性病变正常的大脑充满了葡萄糖和抗坏血酸，这两者都是 在氧化还原金属离子存在下通过自氧化产生晚期糖化终产物（AGE）的来源 催化剂的AGE水平和羧甲基赖氨酸，一种主要的AGE修饰，在 AD患者的大脑AGEs修饰和交联蛋白质，AGEs在两种斑块中均被鉴定， AD大脑的缠结事实上，糖基化有可能成为两者形成的驱动因素。 斑块和缠结。此外，AGEs通过形成活性氧而诱导毒性作用 通过与AGE受体（AGEs）的相互作用，AGEs受体在AD大脑中增加。预防年龄 因此，形成代表了治疗AD的合理方法。 越来越多的人认识到，神经退行性变的进展与神经系统疾病的进展之间存在相似之处。 AD和糖尿病，其中AGE形成是一个可疑的共同致病因素。在当前阶段 II格兰特，我们正在全面测试我们的铅化合物，一个专有的非典型的体内疗效 抑制氧化还原金属离子催化氧化的抗氧化剂，用于治疗糖尿病周围神经病变 使用啮齿动物模型的1型和2型糖尿病。在这篇补充文章中，我们将使用两种不同的动物 AD模型来探索我们的先导化合物的治疗潜力。此应用程序提供了一个 这是一个有利的协同机会，可以将我们最有效的先导化合物的研究扩展到 非糖尿病AD模型。