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: 6423725
• 负责人: EDWARD H. KOO
• 金额: $ 99.81万
• 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/6423725
• 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.

这一新应用是要求提供五年的支持，以寻求一种新型的非甾体类抗炎药（NSAID）在阿尔茨海默氏病（AD）中的作用机理，这是最常见的与年龄相关的痴呆症疾病的形式。越来越多的证据表明，NSAIDS对AD的治疗或预防具有有益的影响。 NSAID作用在AD中的机制尚不清楚，尽管人们普遍认为它们的抗炎特性和环氧酶（COX）抑制作用造成了它们的有益作用。我们的工作假设指出，某些NSAID通过选择性降低脑中淀粉样蛋白β-肽（Abeta42）的致病性42种氨基酸种的水平通过环氧酶（COX）独立机制有用。在初步研究中，我们发现，几种NSAID在培养基或培养的细胞中以高于COX抑制所需的浓度降低了Abeta42的水平。但是，并非所有NSAID（包括新的COX-2选择性抑制剂）共享该属性。实际上，NSAID能够通过靶向基因缺失降低COX-2和COX-2缺乏细胞中的Abeta42水平。重要的是，在转基因小鼠的NSAID中已经证实了体外结果，从而证明了体内组织培养的资金的生理相关性。因此，我们假设Abeta42的减少和抗炎作用是平行机制，共同有助于NSAID在AD中的明显疗效。该计划将通过三个项目严格检验该假设：1）定义NSAID降低Abeta42基础的细胞机制，2）确定化合物，以最大化Abeta42降低属性并在体内测试这些和现有的NSAID，以及3）对这些Abeta42降低人类受试者的影响。