Nitric oxide mimetic NSAIDs for treatment of Alzheimer's Disease

描述(申请人提供)：GT 1061是一种由我们实验室开发的新型治疗剂，最初用于治疗轻至中度阿尔茨海默病(AD)，FDA于2004年批准将其用于健康老年志愿者的I期研究。GT 1061是有机硝酸盐家族中的一员，已在各种动物行为模型中展示了神经保护以及认知和记忆增强特性。在1个模型中，GT 1061逆转了脑室注射b-淀粉样蛋白(AB1-40)所致的大鼠认知功能障碍。硝酸盐是一氧化氮的模拟物，因为许多生物活性都模仿NO；在某些情况下，硝酸盐可以作为NO的供体，产生非常低水平的NO。所谓的NO-NSAIDs(NO供体非类固醇抗炎药)是含有非甾体抗炎药(如氟比洛芬)的硝酸盐，但硝酸盐本身就显示出抗炎活性。我们观察到含有硝酸盐的非甾体抗炎药GT 094在痴呆大鼠模型中增强认知能力，而其他人则报道无氟比洛芬(但不是氟比洛芬本身)减少或清除淀粉样蛋白并调节APP转基因小鼠的小胶质细胞活动。我们观察到GT 094在动物致癌模型中也是一种化学预防抗炎剂。这项建议的目的是开发新的硝酸盐作为AD的抗炎治疗药物，提供认知增强和神经保护。目的1：设计合成新型抗炎硝酸酯类药物(NO模拟非甾体类抗炎药)，研究巨噬细胞中药物降解、炎症和DNA损伤的限制性标志物。目的：通过免疫印迹、认知增强标志物(PERK、pCREB)和炎症标志物(iNOS、MHC-II)检测海马片培养中的药物。目的3：利用胆碱能神经元损伤诱导认知缺陷，在大鼠视觉延迟匹配样本(DMTS)任务中测试药物。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的负载，为将这种候选药物从发现转移到临床提供动力。

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.