Nitric oxide mimetic NSAIDs for treatment of Alzheimer's Disease

描述（由申请人提供）：GT 1061是一种新型治疗剂，在我们的实验室开发，最初针对轻度至中度阿尔茨海默病（AD）的治疗，2004年FDA批准在健康老年志愿者中进行I期研究。GT 1061是有机硝酸盐家族中的一员，在各种动物行为模型中表现出神经保护以及认知和记忆增强特性。在1个模型中，GT 1061逆转了大鼠icv输注b-淀粉样蛋白（Ab 1 -40）产生的认知缺陷。硝酸盐是一氧化氮模拟物，因为许多生物活性模拟NO的生物活性;在某些情况下，硝酸盐可以作为产生非常低水平的NO的NO供体。所谓的NO-NSAID（NO供体非甾体抗炎药）是含有NSAID药物（如氟比洛芬）的硝酸盐，但硝酸盐本身已显示出抗炎活性。我们在痴呆大鼠模型中观察到含有硝酸盐的NSAID GT 094的认知增强，而其他人报道NO-氟比洛芬（但不是氟比洛芬本身）减少或清除APP转基因小鼠中的淀粉样蛋白并调节小胶质细胞活性。我们已经观察到GT 094在动物致癌模型中也是化学预防性抗炎剂。本提案的目的是开发新型硝酸盐作为AD的抗炎治疗剂，其提供认知增强和神经保护。目标1：设计和合成新型抗炎硝酸盐药物（NO模拟NSAID），并研究巨噬细胞培养物中药物降解、炎症和DNA损伤的有限标志物。目标二：在海马切片培养物中测定药物，通过免疫印迹测量认知增强（pERK，pCREB）和炎症（iNOS，MHC-II）的标志物。目的3：在大鼠视觉延迟匹配样本（DMTS）任务中使用胆碱能神经元损伤来检测药物，以诱导认知缺陷。该项目将产生一种候选药物，在随后的研究中，将在转基因模型中测量淀粉样蛋白负荷，为将这种候选药物从发现推向临床提供动力。

DESCRIPTION (provided by applicant): GT 1061 is a novel therapeutic agent, developed in our labs, initially targeted at treatment of mild to moderate Alzheimer's Disease (AD) that was FDA approved for a phase I study in healthy aged volunteers in 2004. GT 1061 is 1 of a family of organic nitrates that have demonstrated neuroprotective as well as cognition-and memory-enhancing properties in a wide variety of animal behavioral models. In 1 model, GT 1061 reversed the cognition deficit produced by icv infusion of b-amyloid (Ab1-40) in rats. Nitrates are nitric oxide mimetics, since much of the biological activity mimics that of NO; and in some circumstances, nitrates may act as NO donors that produce very low levels of NO. So-called NO-NSAIDs (NO-donor non-steroidal anti-inflammatory drugs) are nitrates incorporating an NSAID drug such as flurbiprofen, but nitrates have demonstrated anti-inflammatory activity in their own right. We have observed cognition enhancement by an NSAID containing nitrate, GT 094, in a rat model of dementia, whereas others have reported that NO- flurbiprofen (but not flurbiprofen itself) reduces or clears amyloid and modulates microglial activity in APP transgenic mice. We have observed that GT 094 is also a chemopreventive anti-inflammatory agent in animal carcinogenesis models. It is the objective of this proposal to develop novel nitrates as anti-inflammatory therapeutics for AD, that provide cognition enhancement and neuroprotection. Aim 1: to design and synthesize novel anti-inflammatory nitrate drugs (NO mimetic NSAIDs) and to study limited markers of drug degradation, inflammation, and DNA damage in macrophage cell cultures. Aim 2: to assay drugs in hippocampal slice cultures, measuring by immunoblot, markers of cognition enhancement (pERK, pCREB) and inflammation (iNOS, MHC-II). Aim 3: to test drugs in a rat visual delayed matching to sample (DMTS) task using a cholinergic neuronal lesion to induce a cognitive deficit. This project will yield a drug candidate for which amyloid load will be measured in transgenic models in subsequent research, providing the impetus for moving this drug candidate from discovery to the clinic.