Memantine Therapy for Improved Functional Recovery After TBI

美金刚疗法可改善 TBI 后的功能恢复

• 批准号: 9185232
• 负责人: Milos D Ikonomovic
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 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 2016-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9185232
• 关键词: Acute; Address; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animal Testing; Animals; Area; Astrocytes; Brain; Brain Injuries; Brain region; Brain-Derived Neurotrophic Factor; Cell Count; Cerebrovascular Circulation; Chronic; Clinical; Coenzyme A; Cognition; Cognitive; Cognitive deficits; Complement; Data; Dementia; Development; Dose; Drug usage; Elderly; Encephalitis; Etiology; Experimental Models; FDA approved; Gliosis; Glutamates; Goals; Healthcare Systems; Histopathology; Hour; Human; Image; Imaging Techniques; Impairment; Injection of therapeutic agent; Injury; Intervention; Investigation; Lesion; Life; Link; Lipids; Magnetic Resonance Imaging; Measurement; Measures; Medical Research; Memantine; Memory; Microglia; Modeling; Motor; Mus; N-Methylaspartate; Namenda; Nerve Degeneration; Nervous System Physiology; Neurodegenerative Disorders; Neurologic; Neurological outcome; Neurons; Nootropic Agents; Outcome; Pathogenesis; Pathology; Patients; Peptides; Perfusion; Pharmaceutical Preparations; Pharmacotherapy; Phase; Physiological; Population; Prevention; Principal Investigator; Process; Production; Quality of life; Rattus; Recovery; Recovery of Function; Rehabilitation therapy; Research; Risk; Risk Factors; Rodent; Series; Simvastatin; Spin Labels; Survivors; Synapses; Testing; Therapeutic; Time; Translating; Translations; Traumatic Brain Injury; Traumatic Brain Injury recovery; Treatment Efficacy; Veterans; aspartate receptor; behavior test; cerebrovascular; clinical practice; clinically relevant; cognitive function; controlled cortical impact; density; disability; effective therapy; functional outcomes; hemodynamics; hypoperfusion; improved; inhibitor/antagonist; injured; injury burden; mouse model; nervous system disorder; neurological recovery; neuron loss; neuronal circuitry; neuronal survival; neurotoxic; neurotransmission; prevent; programs; protein metabolite; repaired; research study; response

DESCRIPTION (provided by applicant): Veterans who suffered severe traumatic brain injury (TBI) are burdened by chronic neurological deficits and are at increased risk for developing chronic neurodegenerative disorders such as Alzheimer's disease (AD) later in life. Currently, there are no effective treatments for improving long-term functional recovery and reducing the risk of AD in TBI survivors. Thus, successful rehabilitation of brain-injured veterans and prevention of chronic disability is an area of medical research that warrants intensive investigation. Our preliminary data demonstrated that a single post-injury injection of memantine, an FDA approved drug for treatment of cognitive deficits in AD patients, improved neurological outcome acutely after experimental TBI in rats. However, the degree to which memantine therapy after TBI can improve long-term recovery, enhance neuronal repair and reduce secondary injury processes such as brain inflammation, brain hypoperfusion, and accumulation of amyloid-2 (A2) peptide (all of which contribute to the etiology of AD), remains to be determined. We propose a series of experiments that will directly address these issues by performing experimental controlled cortical impact (CCI) brain injury in rats and in a mouse model of AD. Aim 1: We will perform a dose response analysis of chronic (3 weeks) daily memantine administration on histopathology and neurological recovery in rats after CCI injury (Aim 1a). We will also determine if the beneficial effects of the 3-week treatment will be sustained over an extended chronic (3 month) recovery period, or if prolonged daily treatment is necessary to achieve long-term beneficial effects (Aim 1b). Aim 2: We will assess whether memantine can act as a cognitive enhancer after TBI by administering the drug only during the time of behavioral testing (days 14-19 post injury). We will also determine if potential cognitive enhancing effects are transient or sustained by re-testing the animals 3 months after injury. Aim 3: We will determine if chronic functional outcome after TBI can be improved further by combining memantine therapy with simvastatin therapy, an FDA approved lipid lowering drug. Aim 4: We will examine if memantine and/or combined memantine/simvastatin therapy can suppress post- injury increases in the neurotoxic amyloid-2 (A2) peptide, a molecule central to the pathogenesis of AD. We will achieve this by using a unique mouse model that has been modified genetically to produce human A2 (hA2), which differs from rodent A2 in that it is toxic to neurons and synapses. Aim 5: Analyses proposed in Aim 4 will be complemented by measurements of cerebral blood flow, which is impaired after TBI and influenced by A2 concentrations, and can contribute to the development of AD. In all experiments, we will assess motor, vestibular, and memory function at three weeks and/or three months after injury, as appropriate. Endpoint analyses will include histological analyses of lesion size, cell number, synapse density, microglia/astrocyte activation, A2 concentrations, as well as levels of recovery-promoting brain derived neurotrophic factor and soluble amyloid precursor protein alpha. Collectively, these experiments will determine if chronic memantine therapy is an effective way of improving rehabilitation after TBI, allowing for its quick translation into clinical practice for treatment of injured veterans.

描述（由申请人提供）： 遭受严重创伤性脑损伤 (TBI) 的退伍军人患有慢性神经缺陷，并且在以后的生活中患阿尔茨海默氏病 (AD) 等慢性神经退行性疾病的风险增加。目前，尚无有效的治疗方法可以改善 TBI 幸存者的长期功能恢复并降低 AD 风险。因此，脑损伤退伍军人的成功康复和慢性残疾的预防是值得深入研究的医学研究领域。我们的初步数据表明，在大鼠实验性 TBI 后，单次损伤后注射美金刚（FDA 批准用于治疗 AD 患者认知缺陷的药物）可显着改善神经系统结果。然而，TBI 后美金刚治疗可以在多大程度上改善长期恢复、增强神经元修复并减少继发性损伤过程，如脑炎症、脑灌注不足和淀粉样蛋白 2 (A2) 肽的积累（所有这些都有助于AD 的病因学）仍有待确定。我们提出了一系列实验，通过在大鼠和 AD 小鼠模型中进行实验性受控皮质冲击 (CCI) 脑损伤来直接解决这些问题。目标 1：我们将进行长期（3 周）每日美金刚给药对 CCI 损伤后大鼠组织病理学和神经恢复的剂量反应分析（目标 1a）。我们还将确定 3 周治疗的有益效果是否会在延长的慢性（3 个月）恢复期内持续，或者是否需要延长每日治疗才能实现长期有益效果（目标 1b）。目标 2：我们将通过仅在行为测试期间（受伤后 14-19 天）给药来评估美金刚是否可以作为 TBI 后的认知增强剂。我们还将通过在受伤后 3 个月重新测试动物来确定潜在的认知增强作用是短暂的还是持续的。目标 3：我们将确定通过将美金刚疗法与 FDA 批准的降脂药物辛伐他汀疗法相结合，是否可以进一步改善 TBI 后的慢性功能结果。目标 4：我们将检查美金刚和/或美金刚/辛伐他汀联合治疗是否可以抑制神经毒性淀粉样蛋白 2 (A2) 肽损伤后的增加，神经毒性淀粉样蛋白 2 (A2) 肽是 AD 发病机制的核心分子。我们将通过使用一种独特的小鼠模型来实现这一目标，该模型经过基因改造以产生人类 A2 (hA2)，它与啮齿动物 A2 的不同之处在于它对神经元和突触有毒。目标 5：目标 4 中提出的分析将通过脑血流量测量进行补充，脑血流量在 TBI 后受损并受到 A2 浓度的影响，并可能促进 AD 的发展。在所有实验中，我们将酌情在受伤后三周和/或三个月评估运动、前庭和记忆功能。终点分析将包括病变大小、细胞数量、突触密度、小胶质细胞/星形胶质细胞活化、A2浓度以及促进恢复的脑源性神经营养因子和可溶性淀粉样前体蛋白α水平的组织学分析。总的来说，这些实验将确定慢性美金刚疗法是否是改善 TBI 后康复的有效方法，从而使其能够快速转化为治疗受伤退伍军人的临床实践。