Innovative memantine therapy for neuroprotective effects against ischemic stroke and Alzheimer's disease

创新美金刚疗法对缺血性中风和阿尔茨海默病具有神经保护作用

• 批准号: 10480182
• 负责人: Shan P. Yu
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-11-01 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10480182
• 关键词: APP-PS1; Acceleration; Accounting; Acute; Affinity; Aging; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease therapy; Amyloid beta-Protein; Animal Model; Animals; Apoptotic; Area; Attention; Basic Science; Behavioral; Blood flow; Brain; Brain Diseases; Brain imaging; Cause of Death; Chronic; Clinical; Clinical Treatment; Clinical Trials; Contingent Negative Variation; Control Groups; Data; Dementia; Deterioration; Development; Disease; Disease Progression; Early treatment; Elderly; Electrophysiology (science); FDA approved; Failure; Female; Glutamates; Hour; Hyperactivity; Individual; Infarction; Inflammation; Inflammatory; Investigation; Ischemia; Ischemic Stroke; Mediating; Medical; Memantine; Memory; Molecular; Monitor; Mus; N-Methyl-D-Aspartate Receptors; NMDA receptor antagonist; Neurodegenerative Disorders; Neurons; Neuroprotective Agents; Outcome; Pathogenicity; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Physiological; Population; Predisposition; Preventive treatment; Process; Reaction; Recommendation; Recovery; Reporting; Research; Risk Factors; Safety; Signal Transduction; Slice; Social Behavior; Stage Grouping; Stroke; Symptoms; Synaptic plasticity; Testing; Therapeutic; Time; Veterans; abeta deposition; aging population; antagonist; clinical application; clinical translation; cognitive function; comorbidity; disability; drinking water; effective therapy; excitotoxicity; experience; experimental study; high risk; improved; innovation; male; mild cognitive impairment; military veteran; mouse model; nervous system disorder; neural network; neuron loss; neuroprotection; neurovascular; neurovascular unit; novel; novel therapeutics; post stroke; post stroke cognitive impairment; post stroke dementia; post stroke depression; pre-clinical research; preconditioning; protective effect; psychologic; receptor; regenerative; sham surgery; stroke model; stroke patient; stroke risk; symptom treatment; tau Proteins; therapeutic target; translational potential

Two of most common neurological diseases among aging veterans are Alzheimer’s disease (AD) and stroke. Unfortunately, there are limited clinical treatments for either of these diseases. Clinically, AD and stroke are most likely to strike the same individuals of the aging population. The comorbidity of these two devastating diseases in the same patients represents a greater challenge for pre-clinical research and clinical treatments. Noticeably, AD and stroke share some common pathophysiological mechanisms such as NMDA receptor (NMDAR) hyperactivation-induced excitotoxicity, inflammation, and neurovascular destructions. These two neurological disorders, however, have been investigated mainly in separate research fields. The interplay of AD and stroke have rarely been studied, while both are in urgent needs for effective treatments. Memantine (MEM) is an FDA approved NMDAR antagonist, recommended as a symptomatic treatment for moderate to severe AD patients. MEM, like other NMDAR antagonists but with unique safety record in clinical applications, is highly neuroprotective against ischemic stroke. A significant dilemma is that a NMDAR antagonist has to be administered before or soon (≤3 hours) after the onset of stroke, which is generally impractical in clinical settings. In this exploratory high potential project, we propose to test the novel hypothesis that early MEM treatment at mild and moderate AD stages can have dual efficacy of ameliorating AD progression while priming (preconditioning) the AD brain for enhanced tolerance against ischemic attack that may occur at any time to >50% AD patients. In a typical AD model of 5xFAD mouse of 4 months old (mild stage group) and 6 months old (moderate stage group), MEM (10 mg/kg/day) will be given in drinking water for 1 month to mimic chronic AD treatment. Mice will then be subjected to focal ischemic stroke and the protective effect of the MEM pre-treatment against stroke will be evaluated 3 and 28 days later in comparison to control groups. In long-term experiments with continued MEM, the AD pathology progression, neurovascular deterioration, key molecular signals, inflammatory factors, and psychological/cognitive functions will be monitored up to 2 months after stroke. The therapeutic strategy targeting NMDAR hyperactivity and brain preconditioning is supported by compelling basic and clinical evidence, while the MEM dual effect therapy for AD and stroke has not been investigated before. Being an FDA approved drug, the anti-AD and anti-stroke MEM treatment is expected to have a high translational potential readily leading to consequent clinical trials and a game- change approach for veterans who are susceptible to AD and stroke. It will support more cross-field investigations for a better understanding of interactive mechanisms and identifying more therapeutic targets in the comorbidity of these two neurological diseases.

老年退伍军人中最常见的两种神经系统疾病是阿尔茨海默氏病（AD）和中风。 不幸的是，这两种疾病中的任何一种都有有限的临床治疗方法。临床上，广告和中风是 最有可能击中老龄化人口的同一个人。这两个毁灭性的合并症 同一患者中的疾病代表了临床前研究和临床治疗的更大挑战。 值得注意的是，AD和中风共享一些常见的病理生理机制，例如NMDA接收器 （NMDAR）过度激活引起的兴奋性，感染和神经血管破坏。这两个 但是，神经系统疾病主要在不同的研究领域进行了研究。相互作用 广告和中风很少被研究，而两者都迫切需要有效治疗。美容 （MEM）是FDA批准的NMDAR拮抗剂，建议作为现代症状治疗 严重的广告患者。 MEM，与其他NMDAR拮抗剂一样，但在临床应用中具有独特的安全记录， 对缺血性中风具有高度神经保护作用。一个重大困境是NMDAR拮抗剂必须 中风开始之前或很快（≤3小时），在临床上通常不切实际（≤3小时） 设置。在这个探索性的高潜力项目中，我们建议测试早期元素的新假设 轻度和中等广告阶段的治疗可以具有改善AD进展的双重效率 启动（预处理）广告大脑，以增强可能发生在任何情况下的缺血性攻击的耐受性 是时候> 50％的AD患者了。在4个月大的5xFAD小鼠的典型AD模型中（轻度阶段组）和6个 几个月大（中度舞台组），MEM（10 mg/kg/day）将在饮用水中给出1个月的模仿 慢性广告处理。然后，小鼠将受到局灶性缺血性中风，并受到保护的保护作用 与对照组相比，将在3和28天后评估针对中风的MEM预处理。 长期实验持续MEM，AD病理进展，神经血管定义，关键 分子信号，炎症因子和心理/认知功能将被监测多达2个 中风后几个月。针对NMDAR多动症和大脑预处理的理论策略是 由令人信服的基本证据和临床证据支持，而MEM双重效应疗法的AD和中风疗法 以前没有进行调查。作为FDA批准的药物，抗AD和抗中风MEM治疗 预计将具有很高的翻译潜力，从而导致临床试验和游戏 - 对于容易受到广告和中风的退伍军人的改变方法。它将支持更多的跨场 调查以更好地理解交互式机制并确定更多的治疗目标 在这两种神经系统疾病的合并症中。