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

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，对这两种疾病的临床治疗都是有限的。临床上，AD和中风是 最有可能打击的是老龄化人口中的相同个体。这两种疾病的共病是毁灭性的 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，阿尔茨海默病和中风有一些共同的病理生理机制，如NMDA受体 (NMDAR)过度激活导致兴奋性毒性、炎症和神经血管破坏。这两个 然而，神经性疾病主要是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，而这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，建议作为中度至 重度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， 对缺血性中风有高度的神经保护作用。一个重要的两难境地是，NMDAR的对手必须 在中风发作之前或之后不久(≤3小时)给药，这在临床上通常是不切实际的 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 在轻度和中度AD阶段进行治疗可以具有改善AD进展的双重效果，而同时 启动(预适应)AD大脑，以增强对任何可能发生的缺血发作的耐受性 50%的AD患者的治疗时间。在4个月龄(轻度组)和6个月龄的5xFAD小鼠的典型AD模型中 3个月龄组(中级组)，给予MEM(10 mg/kg/d)在饮水中模拟1个月。 慢性AD治疗。小鼠将受到局灶性缺血性卒中的影响，并具有保护作用 与对照组相比，MEM对中风的预治疗将在3天和28天后进行评估。在……里面 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/认知功能的监测将高达2 中风后的几个月。针对NMDAR多动和脑预适应的治疗策略是 有令人信服的基础和临床证据支持，而MEM双效疗法治疗AD和中风 之前没有被调查过。作为FDA批准的药物，抗AD和抗中风的MEM治疗 预计具有很高的翻译潜力，很容易导致随后的临床试验和游戏- 为易患阿尔茨海默病和中风的退伍军人改变方法。它将支持更多的跨场 为更好地了解相互作用机制和确定更多治疗靶点而进行的调查 这两种神经系统疾病的共病。

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.