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。