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: 8141069
• 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/8141069
• 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 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 neurocognitive 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. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is the most common dementia in the elderly affecting about 10% of those aged 65 or over, for which no treatment is available yet. Under the present situation where the relative proportion of elderly is progressively increasing, AD has become a significant problem in the aging population of veterans and seniors. Therefore, the study of this disease is very relevant to the overall mission of Veterans Administration. Evidence indicates that AD implicates vascular complications leading to impaired cerebral blood flow, in turn suggesting that early intervention of vascular dysfunction would be critical as therapeutics for AD therapeutics. Here, we propose to evaluate the therapeutic potential of S-nitrosoglutathione, an endogenous nitric oxide carrier, against cerebrovascular complications associated with development of AD. We expect that this approach will lead to the development of a new strategy for the treatment of AD which will provide benefits for the healthcare of elderly Veterans and seniors.

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，影响约 10% 的 65 岁或以上老年人，但目前尚无延缓或阻止该疾病进展的治疗方法。老年人口的比例逐渐增加，AD已成为包括退伍军人在内的老年人的一个重要问题，因此，对该疾病的研究与退伍军人管理局的使命相关。最近，新的证据表明脑血管并发症和局部脑损伤。血流量为反过来，这一证据为脑血管功能障碍的早期治疗提供了理论依据，这对于延迟、减缓或预防 AD 的发展至关重要。目前，游离NO供体，例如硝普钠和硝化甘油，正在各种临床环境中使用，但是，这些释放游离NO的NO供体可能。 GSNO 不是 AD 的有效治疗方法，因为伴随的慢性炎症和氧化应激会清除这些供体中的游离 NO，从而产生有害的过氧亚硝酸盐。在此，我们建议评估 GSNO（生物系统中 NO 的主要转运形式）的治疗潜力。 GSNO 的治疗能够通过 S-亚硝基化诱导多种细胞信号转导途径，这些信号转导途径对于 NO 的生物作用至关重要，并且不会产生游离 NO。因此，GSNO 是治疗 AD 相关脑血管并发症的有希望的候选药物，最近我们观察到 GSNO 治疗可抑制炎症反应，并且还可以抑制炎症反应。减少A?慢性脑灌注不足的老年大鼠（一种与迟发性 AD 相关的血管功能障碍动物模型）以及过表达人 A 的转基因小鼠中，A 的积累并改善受损的学习和记忆性能在这些数据的基础上，设计了以下具体目标，以提高 GSNO 在 AD 治疗中的可靠性，优化药理学参数，并研究药物作用的机制。 具体目标 1：确定 GSNO 治疗与阿尔茨海默氏病相关的脑血管并发症的疗效和药理学最佳剂量：在此目标下，我们建议优化 GSNO 治疗与 AD 病理学发生和进展相关的脑血管并发症的疗效。这些研究将采用模型：产生高水平 A¿用于对早发性 AD 和接受双侧颈总动脉闭塞 (BCCAO) 的老年大鼠进行研究，这是人类轻度认知障碍和相关迟发性 AD 的临床相关模型。 具体目标 2：研究 GSNO 治疗的潜在机制：GSNO 抗炎和血管保护活性的意义：在此目标下，我们建议研究 GSNO 介导的抗炎和血管保护活性的潜在机制。脑微血管内皮细胞中的保护性信号级联反应的重点是研究调节炎症介质和 A¿ 基因表达的细胞信号转导介质的 S-亚硝基化。本文描述的研究结果应有助于更好地了解 AD 血管病理学的药理学、生化和细胞生物学事件，以及 GSNO 作为 AD 治疗药物的可能用途。 公共卫生相关性： 阿尔茨海默病（AD）是老年人中最常见的痴呆症，约占65岁以上老年人的10%，目前尚无治疗方法。在目前老年人相对比例逐渐增加的情况下，AD已成为一种常见的痴呆症。因此，对这种疾病的研究与退伍军人管理局的总体使命密切相关。有证据表明，AD 与导致脑血流受损的血管并发症有关，从而表明应进行早期干预。血管功能障碍将是在这里，我们提出了 S-亚硝基谷胱甘肽（一种内源性一氧化氮载体）对抗 AD 相关脑血管并发症的治疗潜力，我们期望这种方法将导致开发一种新的治疗策略。 AD 的治疗将为老年退伍军人和老年人的医疗保健带来好处。