Prostaglandins & Oxidative Damage in ADAPT Participants

前列腺素

• 批准号: 6933146
• 负责人: John C S Breitner
• 金额: $ 31.04万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6933146
• 关键词: Alzheimer' s disease; oxidative stress; prostaglandins

EXCEED THE SPACE PROVIDED. Several large epidemiological studies have associated a profound reduction in the incidence of Alzheimer's Disease (AD) in older individuals who took non-steroidal anti-inflammatory drugs (NSAIDs) for longer than 2 years. However, clinical trials of NSAIDs in patients with established AD failed to show efficacy. This has led to the hypothesis that NSAIDs suppress pathologic processes critical to the initiation of AD and that these processes may be related to inhibition of the cyclooxygenase enzymes and subsequent prostaglandin (PG) production. We propose to test this hypothesis by quantifying endogenous eicosanoid production in subjects enrolled in the Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT), an NIA-sponsored study of NSAIDs in the prevention of AD. Specifically, we will 1) determine the efficacy of selective and non- selective NSAIDs t o suppress 1 evels o f quantitative b iomarkers o f P G p reduction systemically and in t he central nervous system of ADAPT participants; 2) determine the efficacy of NSAIDs to suppress levels of quantitative biomarkers of oxidative damage systemically and in the central nervous system of ADAPT participants; and 3) correlate changes in the levels of biomarkers of PG production and oxidative damage with rates of cognitive decline as determined in ADAPT. We have developed highly accurate and precise mass spectrometric assays to quantify PGs, PG metabolites, and lipid peroxidation products and are routinely performing these assays in our laboratory. These studies will provide important insights into the mechanisms by which NSAIDs prevent AD. PERFORMANCE SITE ========================================Section End===========================================

超出提供的空间。几项大型流行病学研究表明，服用非类固醇抗炎药(NSAIDs)超过2年的老年人阿尔茨海默病(AD)的发病率显著降低。然而，在已确诊的AD患者中进行的非类固醇抗炎药的临床试验并未显示出疗效。这导致了一种假设，即非甾体抗炎药抑制了AD发病的关键病理过程，这些过程可能与抑制环氧合酶和随后的前列腺素(PG)产生有关。我们建议通过量化参与阿尔茨海默病抗炎预防试验(ADTA)的受试者的内源性二十烷酸类化合物来检验这一假设，该试验是一项由NIA赞助的关于非类固醇抗炎药预防AD的研究。具体地说，我们将1)确定选择性和非选择性NSAIDs的有效性，以系统地和在适应参与者的中枢神经系统中抑制P-Gp降低的1个水平的定量生物标志物；2)确定NSAIDs在系统地和在适应参与者的中枢神经系统中抑制氧化损伤的定量生物标记物水平的有效性；以及3)PG产生和氧化损伤生物标记物水平的变化与在Adapt中确定的认知功能减退率的相关性。我们已经开发出高精确度和精确度的质谱学分析方法来定量PGs、PG代谢物和脂质过氧化产物，并在我们的实验室进行常规的这些分析。这些研究将为非类固醇抗炎药预防AD的机制提供重要的见解。表演网站========================================Section End===========================================