Development and Testing of a Novel Neuroprotective Drug

新型神经保护药物的开发和测试

• 批准号: 7140561
• 负责人: DAVID R SCHUBERT
• 金额: $ 21.43万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2007-12-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7140561
• 关键词: Alzheimer' s disease; Huntington' s disease; aging; amyotrophic lateral sclerosis; cAMP response element binding protein; chemoprevention; combinatorial chemistry; disease /disorder model; drug design /synthesis /production; drug screening /evaluation; genetically modified animals; laboratory mouse; memory; neuroprotectants; nonhuman therapy evaluation

DESCRIPTION (provided by applicant): There is a profound need for therapeutics that prevents nerve cell death in diseases of the nervous system. Examples include Alzheimer's and Parkinson's diseases as well as less frequent conditions such as ALS and Huntington's disease. In addition, there are equally intractable conditions such as stroke and non-AD memory loss. Five years ago a novel small organic pharmacophore was discovered in our laboratory that prevents cell death in a variety of nerve cell death tissue culture paradigms, including amyloid toxicity, neurotrophic factor withdrawal, excitotoxicity, glucose starvation, and oxidative stress. The effect of this compound appears to be nerve specific, for it does not block the apoptotic death of fibroblasts caused by TNF-alpha or staurosporine. The goals of this project are to use combinatorial and medicinal chemistry to improve the efficacy of this neuroprotective compound and then to test these improved versions of the compound in animal models of several age-associated neurological diseases, including AD, Huntington's and ALS. In addition, since the compound keeps CREB levels elevated under conditions of stress, its effectiveness in a mouse memory model will be studied. The results from these studies will determine the therapeutic potential of this novel compound.

描述（由申请人提供）：对治疗剂的巨大需求可以防止神经系统疾病中的神经细胞死亡。例子包括阿尔茨海默氏症和帕金森氏病，以及频繁的疾病，例如ALS和亨廷顿氏病。此外，还有同样棘手的条件，例如中风和非AD记忆丧失。五年前，在我们的实验室中发现了一种新型的有机药效团，可防止各种神经细胞死亡组织培养范式中的细胞死亡，包括淀粉样蛋白毒性，神经营养因子戒断，兴奋性毒性，葡萄糖饥饿和氧化应激。该化合物的作用似乎是神经在特定的，因为它不会阻止由TNF-Alpha或Staurosporine引起的成纤维细胞的凋亡死亡。该项目的目标是使用组合和药物化学来提高这种神经保护化合物的疗效，然后在几种与年龄相关的神经系统疾病的动物模型中测试这些改进的化合物，包括AD，Huntington's和ALS。此外，由于该化合物在压力条件下保持CREB水平升高，因此将研究其在鼠标内存模型中的有效性。这些研究的结果将确定这种新颖化合物的治疗潜力。