In Vivo Efficacy of New Neuroprotective Drugs

新型神经保护药物的体内疗效

• 批准号: 7847466
• 负责人: DAVID R SCHUBERT
• 金额: $ 23.44万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7847466
• 关键词: A Mouse; AD transgenic mice; APP-PS1; Address; Age; Age-Months; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Animal Disease Models; Animal Experiments; Animal Model; Animals; Behavior; Behavioral; Biological Assay; Blood - brain barrier anatomy; Brain; Brain-Derived Neurotrophic Factor; Cell Culture Techniques; Cell Death; Chemistry; Clinic; Clinical; Cognitive deficits; Data; Data Set; Databases; Defect; Disease; Dose; Drug Kinetics; Exhibits; Family; Food; Funding; Glucose; Goals; Grant; Hippocampus (Brain); Human; Individual; Ischemia; Laboratories; Lead; Memory; Modeling; Molecular Weight; Motor; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neuroprotective Agents; Older Population; Oryctolagus cuniculus; Oxidative Stress; Pathology; Pharmaceutical Chemistry; Pharmaceutical Preparations; Preclinical Drug Evaluation; Preparation; Public Health; Rattus; Risk Factors; Running; Short-Term Memory; Slice; Solid; Starvation; Stress; Testing; Time; Toxic effect; Transgenic Mice; Transgenic Organisms; United States National Institutes of Health; Withdrawal; Work; combinatorial; cost; drug efficacy; efficacy testing; excitotoxicity; improved; in vivo; motor deficit; nervous system disorder; novel; prevent; public health relevance; research study; small molecule; tau Proteins; therapy development

DESCRIPTION (provided by applicant): Diseases of the nervous system caused by nerve cell death represent a growing concern because of their association with our increasingly older population. There are currently few, if any, drugs that are able to cross the blood-brain barrier and prevent nerve cell death associated with diseases like Alzheimer's. With the support of a R21 grant, over the past few years our laboratory has synthesized two novel small organic compounds that prevent nerve cell death in a wide variety of toxic stress cell culture assays. These compounds have an activity similar to brain derived neurotrophic factor and prevent nerve cell death associated with trophic factor withdrawal, excitotoxicity, glucose starvation, oxidative stress, and both intra- and extra-cellular amyloid toxicity. Our best lead in this group has an EC50 of below 10 nanomolar in some assays and also stimulates LTP in hippocampal slice preparations. The other lead compound was shown to enhance memory in rats in addition to its neuroprotective activities. Preliminary experiments from two outside laboratories and one from our own indicate that both of our compounds may have the ability to reduce cognitive deficits or A21-42 accumulation in AD animal models. One compound also is protective in a rabbit ischemia model. While a previous R21 supported the chemistry and some animal work (memory and PK studies), there were neither sufficient time nor funds to fully explore the efficacy of these compounds in an animal model of neurodegenerative disease. To address this important issue, we will test the two compounds in two animal models of neurological disease related to Alzheimer's, an AD human APP/PS1 transgenic line and a mouse line exhibiting tau pathology. This work will allow us to determine the potential for this novel class of drugs for further clinical development for the treatment of AD. If either one or both drugs are successful in one or more of the animal models, we will then apply for a U01 grant in order to push them toward IND approval and the clinic. PUBLIC HEALTH RELEVANCE: There is a great need for drugs for the treatment of age-associated neurodegenerative diseases such as Alzheimer's disease. During the past few years our laboratory has discovered two very potent drugs that have great potential for the treatment of this disease, and we are requesting funds to test the efficacy of these drugs in two animal models of Alzheimer's. These are experiments that are required for us to move these drugs toward the clinic.

描述(申请人提供)：神经细胞死亡引起的神经系统疾病越来越令人担忧，因为它们与我们日益老龄化的人口有关。目前，很少有药物能够跨越血脑屏障，防止与阿尔茨海默氏症等疾病相关的神经细胞死亡。在R21拨款的支持下，我们的实验室在过去几年中合成了两种新的小型有机化合物，在各种毒性应激细胞培养分析中防止神经细胞死亡。这些化合物具有类似于脑源性神经营养因子的活性，可以防止与营养因子停用、兴奋毒性、葡萄糖饥饿、氧化应激以及细胞内和细胞外淀粉样蛋白毒性相关的神经细胞死亡。我们这组中最好的铅在某些检测中的EC50低于10纳摩尔，并在海马片制备中刺激LTP。另一种铅化合物被证明除了具有神经保护活性外，还能增强大鼠的记忆。来自两个外部实验室和我们自己的一个实验室的初步实验表明，我们的两个化合物都可能具有减少AD动物模型中认知缺陷或A21-42积聚的能力。一种化合物在兔脑缺血模型中也具有保护作用。虽然之前的R21支持化学和一些动物工作(记忆和PK研究)，但没有足够的时间和资金来充分探索这些化合物在神经退行性疾病动物模型中的疗效。为了解决这个重要的问题，我们将在两个与阿尔茨海默氏症相关的神经疾病动物模型中测试这两种化合物，一个是AD人类APP/PS1转基因系，另一个是表现出tau病理的小鼠系。这项工作将使我们能够确定这类新药进一步临床开发治疗AD的潜力。如果其中一种或两种药物在一个或多个动物模型中成功，我们将申请U01拨款，以推动它们获得IND批准和临床。 公共卫生相关性：非常需要治疗阿尔茨海默病等与年龄相关的神经退行性疾病的药物。在过去的几年里，我们的实验室发现了两种非常有效的药物，它们在治疗这种疾病方面具有巨大的潜力，我们正在申请资金，以在两种阿尔茨海默氏症动物模型上测试这些药物的疗效。这些实验是我们将这些药物推向临床所必需的。