Novel mechanisms of NSAID action in Alzheimer disease

NSAID 在阿尔茨海默病中作用的新机制

• 批准号: 6706317
• 负责人: EDWARD H. KOO
• 金额: $ 118.24万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6706317
• 关键词: Alzheimer' s disease; amyloid proteins; brain disorder chemotherapy; chemoprevention; neuropharmacology; nonsteroidal antiinflammatory agent

This new application is to request for five years support to pursue a novel mechanism of action of non-steroidal anti-inflammatory drugs (NSAIDs) in Alzheimer's disease (AD), the most common form of age- related dementing illness. Increasing evidence suggests that NSAIDs have beneficial effects in the treatment or prevention of AD. The mechanisms of NSAID action in AD are unknown although it is widely believed that their anti-inflammatory properties and cyclo-oxygenase (COX) inhibition account for their beneficial effects. Our working hypothesis states that certain NSAIDs are useful in AD therapy by selectively reducing the levels of the pathogenic 42 amino acid species of amyloid beta-peptide (Abeta42) in brain through a cyclo-oxygenase (COX) independent mechanism. In preliminary studies, we found that several NSAIDs reduced the levels of Abeta42 in medium or cultured cells at concentrations above that required for COX inhibition. However, this property was not shared by all NSAIDs, including the newer COX-2 selective inhibitors. Indeed, NSAIDs were able to reduce Abeta42 levels in cell deficient in COX-2 and COX-2 by targeted gene deletions. Importantly, the in vitro results have been confirmed in short term studies of NSAIDs in transgenic mice, thereby demonstrating the physiological relevance of the tissue cultured funding in vivo. Therefore, we hypothesize that Abeta42 reduction and anti-inflammatory effects are parallel mechanisms that together contribute to the apparent efficacy of NSAIDs in AD. The program will rigorously test this hypothesis through three Projects: 1) define the cellular mechanisms that underlie Abeta42 reduction by NSAIDs, 2) identify compounds that maximize the Abeta42 reducing property and test these and existing NSAIDs in vivo, and 3) characterize these Abeta42 lowering effects in human subjects.

这项新的申请是为了寻求一种新的非甾体抗炎药（NSAIDs）治疗阿尔茨海默病（AD）的作用机制，这是一种最常见的与年龄相关的痴呆疾病。越来越多的证据表明，非甾体抗炎药在治疗或预防AD方面有有益的作用。非甾体抗炎药在AD中的作用机制尚不清楚，尽管人们普遍认为它们的抗炎特性和环加氧酶（COX）抑制作用是其有益作用的原因。我们的工作假设表明，某些非甾体抗炎药通过不依赖于环加氧酶（COX）的机制，选择性地降低大脑中淀粉样蛋白β肽（Abeta42）的42种致病性氨基酸的水平，从而有助于AD的治疗。在初步研究中，我们发现几种非甾体抗炎药降低了培养基或培养细胞中Abeta42的水平，浓度高于COX抑制所需的浓度。然而，并非所有非甾体抗炎药都具有这种特性，包括较新的COX-2选择性抑制剂。事实上，非甾体抗炎药能够通过靶向基因缺失来降低缺乏COX-2和COX-2的细胞中Abeta42的水平。重要的是，非甾体抗炎药在转基因小鼠体内的短期研究证实了体外结果，从而证明了组织培养资金在体内的生理相关性。因此，我们假设Abeta42的减少和抗炎作用是平行的机制，共同促成了非甾体抗炎药对AD的明显疗效。该计划将通过三个项目严格验证这一假设：1)确定非甾体抗炎药减少Abeta42的细胞机制；2)鉴定最大限度地减少Abeta42的化合物并在体内测试这些化合物和现有的非甾体抗炎药；3)表征这些降低Abeta42在人类受试者中的作用。