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病（AD）和中风。 不幸的是，这两种疾病的临床治疗方法都很有限。临床上，AD和中风 最有可能袭击老龄化人口中的同一个人。这两种毁灭性的共病 同一患者的疾病对临床前研究和临床治疗提出了更大的挑战。 值得注意的是，AD 和中风具有一些共同的病理生理机制，例如 NMDA 受体 (NMDAR) 过度激活引起的兴奋性毒性、炎症和神经血管破坏。这两个 然而，神经系统疾病主要在不同的研究领域进行研究。的相互作用 AD 和中风很少被研究，而两者都迫切需要有效的治疗。美金刚 (MEM) 是 FDA 批准的 NMDAR 拮抗剂，推荐作为中度至中度患者的对症治疗 严重AD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。一个重要的困境是 NMDAR 拮抗剂必须 在卒中发作前或卒中后不久（≤3小时）给药，这在临床上通常不切实际 设置。在这个探索性的高潜力项目中，我们建议测试早期 MEM 的新假设 轻度和中度 AD 阶段的治疗可以具有改善 AD 进展的双重功效，同时 启动（预处理）AD 大脑，以增强对随时可能发生的缺血性发作的耐受性 > 50% AD 患者的时间。在 4 个月大（轻度组）和 6 个月大的 5xFAD 小鼠的典型 AD 模型中 月龄（中期组），MEM（10 mg/kg/天）将通过饮用水给予 1 个月以模仿 慢性AD治疗。然后小鼠将遭受局灶性缺血性中风，并且这些药物的保护作用 MEM 针对中风的预处理将在 3 天和 28 天后与对照组进行比较评估。在 持续MEM的长期实验、AD病理进展、神经血管恶化、关键 分子信号、炎症因子和心理/认知功能将被监测最多 2 中风后几个月。针对 NMDAR 过度活跃和大脑预处理的治疗策略是 有令人信服的基础和临床证据支持，而 MEM 对 AD 和中风的双效疗法 之前没有调查过。作为 FDA 批准的药物，抗 AD 和抗中风 MEM 治疗 预计具有很高的转化潜力，很容易导致随后的临床试验和游戏- 改变易患 AD 和中风的退伍军人的方法。它将支持更多跨领域 为了更好地理解相互作用机制并确定更多治疗靶点的研究 这两种神经系统疾病的共病。