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: 8398957
• 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/8398957
• 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; Veterans; aged; aging population; artery occlusion; base; biological systems; cerebral hypoperfusion; cerebrovascular; clinically relevant; design; effective therapy; hemodynamics; improved; innovation; interest; mild cognitive impairment; mutant; oxidative damage; prevent; protective effect; public health relevance; 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)： 阿尔茨海默病(AD)是老年人中最常见的痴呆症，在65岁或以上的人中约有10%受到影响，但目前还没有延缓或阻止疾病进展的治疗方法。在目前老年人口比例逐步增加的情况下，AD已经成为包括退伍军人在内的老年公民面临的一个重大问题。因此，对这种疾病的研究关系到退伍军人管理局的使命。近年来，新的证据表明脑血管并发症和局部脑血流受损是AD的致病因素，并伴随着记忆丧失和行为改变。反过来，这一证据为脑血管功能障碍的早期治疗提供了理论基础，而脑血管功能障碍对于延缓或预防AD的发展至关重要。一氧化氮(NO)在维持血管张力和血流动力学中起重要作用。目前，硝普钠和硝酸甘油等游离NO供体正被用于各种临床环境。然而，这些释放游离NO的NO供体可能不是治疗AD的有效方法，因为伴随而来的慢性炎症和氧化应激清除了这些供体的游离NO，产生了有害的过氧亚硝酸盐。在这里，我们建议评估GSNO的治疗潜力，GSNO是NO在生物系统中的主要运输形式，用于治疗AD。GSNO可通过S转亚硝化作用诱导多种细胞信号转导途径，而不产生游离NO。此外，在各种疾病条件下，GSNO还具有抗炎、抗氧化和血管保护作用。因此，GSNO可作为AD相关脑血管并发症的独立治疗药物。作为支持，我们最近观察到，GSNO治疗在慢性脑低灌流老年大鼠(与晚发性AD相关的血管功能障碍的动物模型)和过度表达人A？的转基因小鼠中抑制炎症反应，还减少A？的积累，并改善学习和记忆能力受损。在这些数据的基础上，设计了以下具体目标，以提高GSNO治疗AD的疗效可靠性，优化药理参数，并探讨其药物作用机制(S)。 具体目标1：确定GSNO治疗阿尔茨海默病相关脑血管并发症的疗效和最佳药理剂量：在此目标下，我们建议优化GSNO治疗与AD病理发生发展相关的脑血管并发症的疗效。这些研究将使用两种动物模型：用于研究早发性AD的转基因小鼠和双侧颈总动脉闭塞(BCCAO)的老年大鼠，BCCAO是一种临床相关的人类轻度认知障碍和相关迟发性AD的模型。 特定目的2：研究GSNO治疗的机制(S)：GSNO抗炎和血管保护作用的意义：在此基础上，我们建议研究GSNO介导的脑微血管内皮细胞抗炎和血管保护信号转导的机制(S)。这一目标的重点将是研究细胞信号介质的S-亚硝化，调节炎症介质的基因表达，并清除血脑屏障(BBB)。本文描述的研究结果将有助于更好地了解AD血管病理基础上的药理学、生化和细胞生物学事件，以及GSNO作为治疗AD的治疗药物的可能性。