Development of S-Nitrosothiol-based Therapy for Alzheimer's Disease

基于 S-亚硝基硫醇的阿尔茨海默病疗法的开发

• 批准号: 8696815
• 负责人: Avtar K Singh
• 金额: --
• 依托单位: RALPH H JOHNSON VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8696815
• 关键词: Affect; Aging; Alzheimer' s Disease; Amyloid beta-Protein; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Behavioral; Bilateral; Biochemical; Biological; Biological Availability; Blood - brain barrier anatomy; Blood Vessels; Brain; Cells; Cerebrovascular Circulation; Cerebrum; Chronic; Clinical; Common carotid artery; Cyclic GMP; Data; Databases; Dementia; Deposition; Development; Disease; Disease Progression; Disodium Salt Nitroprusside; Dose; Drug effect disorder; Early Intervention; Early treatment; Elderly; Endothelial Cells; Endothelium; Event; Functional disorder; Gene Expression; Generations; Healthcare; Human; Inflammation; Inflammation Mediators; Inflammatory Response; Investigation; Laboratories; Late Onset Alzheimer Disease; Lead; Learning; Maintenance; Mediating; Mediator of activation protein; Memory; Memory Loss; Mission; Modeling; Nitric Oxide; Nitric Oxide Donors; Nitroglycerin; Oxidation-Reduction; Oxidative Stress; Pathology; Pathway interactions; Penicillamine; Performance; Peroxonitrite; Play; Population; Presenile Alzheimer Dementia; Proteins; Rattus; Reaction; Relative (related person); Reperfusion Injury; Reporting; Role; S-Nitrosoglutathione; S-Nitrosothiols; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Superoxides; Supplementation; Therapeutic; Tissues; Transgenic Mice; Treatment Efficacy; United States Department of Veterans Affairs; Vascular Diseases; Veterans; aged; aging population; artery occlusion; base; biological systems; cerebral hypoperfusion; cerebrovascular; clinically relevant; design; effective therapy; endothelial dysfunction; hemodynamics; improved; innovation; interest; mild cognitive impairment; mutant; oxidative damage; prevent; protective effect; treatment strategy

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common form of dementia in the elderly, affecting about 10% of those aged 65 or over, but no treatment to delay or halt the progression of the disease is as yet available. Under the present situation where the proportion of the elderly population is progressively increasing, AD has become a significant problem for the elderly citizens including Veterans. Therefore, the study of this disease is relevant to the mission of the Veterans Administration. Recently, new evidences indicate cerebrovascular complications and impaired regional cerebral blood flow as the causative factors in AD along with its associated memory loss and behavioral changes. In turn, this evidence provides the rationale for early treatment of cerebrovascular dysfunction which is critical for delaying, slowing down or preventing the development of AD. Nitric oxide (NO) plays an essential role in the maintenance of vascular tone and hemodynamics. Currently, free NO donors, such as sodium nitroprusside and nitroglycerine, are being used in various clinical settings. However, these NO donors, releasing free NO, may not be an effective treatment for AD because the concomitant chronic inflammation and oxidative stress scavenge free NO from these donors to generate deleterious peroxynitrite. Here, we propose to evaluate the therapeutic potential of GSNO, a major transport form of NO in biological systems, for the treatment of AD. GSNO is able to induce several cell signal transduction pathways that are essential for biological action of NO via S-transnitrosylation without generation of free NO. In addition, GSNO is implicated in anti-inflammatory, anti-oxidant, and vaso-protective effects under various disease conditions. Therefore, GSNO is a promising candidate as a stand-alone therapy for cerebrovascular complications implicated in AD. In support, we have recently observed that GSNO treatment inhibited the inflammatory response and also reduced A¿ accumulation and improved impaired learning and memory performance in aged rats with chronic cerebral hypoperfusion, an animal model for vascular dysfunction associated with late-onset AD, and in transgenic mice over-expressing human A¿. On the basis of these data, the following specific aims are designed to improve therapeutic reliability of GSNO in the treatment of AD, to optimize pharmacological parameters, and to investigate mechanisms underlying the drug action(s). Specific Aim 1: To establish therapeutic efficacy and pharmacological optimal dose of GSNO therapy for cerebrovascular complications associated with Alzheimer's disease: Under this aim, we propose to optimize the efficacy of GSNO treatment against cerebrovascular complications associated with development and progression of AD pathology. Two animal models will be employed for these studies: transgenic mice producing high levels of A¿ for studies of early-onset AD and aged rats received bilateral common carotid artery occlusion (BCCAO), a clinically relevant model for human mild cognitive impairment and associated late-onset AD. Specific Aim 2: To investigate the mechanism(s) underlying GSNO therapy: Implication of anti-inflammatory and vaso-protective activities of GSNO: Under this aim, we propose to investigate the mechanism(s) underlying GSNO mediated anti-inflammatory and vaso-protective signaling cascades in brain micro-vessel endothelial cells. Focus of this aim will be to study the S-nitrosylation of cell signaling mediators regulating gene expression for inflammatory mediators and A¿ clearance across the blood brain barrier (BBB). The results from studies described here should provide a better understanding of pharmacological, biochemical and cell biological events underlying vascular pathology of AD, and the possible utility of GSNO as therapeutics for the management of AD.

描述（由申请人提供）： 阿尔茨海默氏病（AD）是古老的痴呆症最常见的形式，影响了65岁或以上的患者中约10％，但没有延迟或停止这种疾病进展的治疗方法。在当前的情况下，最古老的人口比例正在逐渐增加，广告已成为包括退伍军人在内的古老公民的重要问题。因此，对该疾病的研究与退伍军人管理局的任务有关。最近，新的证据表明脑血管并发症和区域脑血流受损，作为AD的关键因素以及其相关的记忆丧失和行为变化。反过来，该证据为早期治疗脑血管功能障碍提供了理由，这对于延迟，减慢或阻止AD的发展至关重要。一氧化氮（NO）在维持血管张力和血液动力学中起着至关重要的作用。目前，在各种临床环境中都使用了免费的无捐助者，例如亚硝化钠和硝酸甘油。但是，这些没有释放免费的捐赠者可能不是AD的有效治疗方法，因为伴随着慢性炎症和氧化应激清除毫无用处，可以从这些捐赠者那里产生有害的过氧亚硝酸盐。在这里，我们建议评估生物系统中NO的主要运输形式GSNO的治疗潜力，用于治疗AD。 GSNO是否有可能诱导几种细胞信号转导途径，这对于无需自由no的生物转硝基化而对生物学作用至关重要。此外，在各种疾病条件下，GSNO在抗炎，抗氧化剂和血管保护作用中实施。因此，GSNO是作为AD中实施的脑血管并发症的独立疗法的承诺候选者。为了支持，我们最近观察到，GSNO治疗抑制了炎症反应，并减少了A的累积，并改善了患有慢性脑灌注不足的老年大鼠的学习和记忆表现，这是一种与晚期发炎AD相关的血管功能障碍的动物模型，以及与过度表达过表达人类的转基因小鼠相关的动物模型。根据这些数据，以下特定目的旨在提高GSNO在AD治疗中的治疗可靠性，优化药物参数以及研究药物作用（S）基础的机制（S）。 具体目的1：为了建立与阿尔茨海默氏病有关的脑血管并发症的GSNO治疗的治疗效率和药物最佳剂量：在此目的下，我们建议优化GSNO治疗抗脑血管并发症的有效性，与广告病理的发展和进展相关。这些研究将采用两种动物模型：产生高水平A的转基因小鼠进行早期发作的AD研究和老年大鼠接受双侧共同颈动脉闭塞（BCCAO），这是一种临床相关的人类轻度认知障碍和相关晚期AD的临床相关模型。 具体目的2：研究GSNO疗法的基本机制：GSNO的抗炎和VASO保护活性的影响：在此目标下，我们建议研究GSNO介导的抗炎和VASO抗炎和VASO介导的机制，该机制在脑部微型无神化细胞中的抗炎和VASO信号壳细胞。该目的的重点是研究调节炎症介质基因表达的细胞信号介质的S-硝基化，并在整个血脑屏障（BBB）中清除率。此处描述的研究的结果应更好地了解AD的血管病理基础的药物，生化和细胞生物学事件，以及GSNO作为AD治疗的治疗方法。