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 阿尔茨海默氏病（AD）的特征是进行性认知功能障碍和宽度神经元 损失，淀粉样B斑块的积累以及热磷酸化的TAU聚集到神经纤维中 人们对使用抗氧化剂来治疗AD和其他抗氧化剂一直很感兴趣 神经退行性病理。正常的大脑被葡萄糖和抗坏血酸盐代替，这两个都是 在存在氧化还原金属离子的情况下，通过自动氧化的晚期糖基化终产物来源（年龄） 催化剂。年龄水平和羧甲基赖氨酸是一种主要的年龄变化，在 广告患者的大脑。在两个斑块和 广告大脑的缠结。实际上，糖基有可能在两者的形成中产生驱动影响 斑块和缠结。此外，年龄会通过形成活性氧诱导有毒作用 通过与年龄接收器（愤怒）的相互作用，这些接收器在广告大脑中增加。预防年龄 因此，形成代表了治疗AD的合理方法。 人们越来越认识到神经退行性的进展之间存在相似之处 随着年龄的形成，AD和糖尿病是一种可疑的共同基制造商。在我们目前的阶段 ii Grant，我们正在全面测试铅化合物的体内效率，这是一个专有的非典型化合物 抑制氧化氧化金属离子催化的抗氧化剂，对糖尿病周围神经病 使用1型和2型糖尿病的啮齿动物模型。在这种补充中，我们将使用两种不同的动物 探索铅化合物的治疗潜力的AD模型。该应用程序提供 充满活力和协同的机会，将我们最有力的铅综合综合的投资扩展到 非糖尿病AD模型。