Novel NMDA Antagonists to Treat Stroke

治疗中风的新型 NMDA 拮抗剂

基本信息

批准号：
8696785
负责人：
Piyush M Patel
金额：
--
依托单位：
VA SAN DIEGO HEALTHCARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8696785
关键词：
Acute Advanced Glycosylation End Products Age Agonist Aldehyde-Lyases Alteplase Alzheimer&apos s Disease Amino Acid Neurotransmitters Animal Model Animals Attenuated Axura Behavior Behavioral Binding Biochemical Biochemical Pathway Biological Assay Blood Brain Brain Edema Brain Injuries Cell Survival Cerebral Ischemia Cerebral hemisphere hemorrhage Cerebrovascular Disorders Cerebrum Clinical Clinical Investigator Clinical Trials Coagulation Process Combined Modality Therapy Complication Data Dicarboxylic Acids Dose Embolism Enzyme Inhibitor Drugs Enzyme Inhibitors European Evolution Excitatory Amino Acid Antagonists Excitatory Amino Acids FDA approved Failure Frequencies Fright Future Gel Generations Glutamates Hematoxylin and Eosin Staining Method Hemoglobin Hemorrhage Histological Techniques Human Incidence Infarction Injury Intravenous Investigation Ischemia Ischemic Stroke Korean War Label Left Marketing Measures Mediating Medical Memantine Methods Modality Modeling Molecular Target Monitor Morbidity - disease rate N-Methyl-D-Aspartate Receptors N-Methylaspartate Namenda Nerve Degeneration Oryctolagus cuniculus Outcome Oxidoreductase Pathology Pathway interactions Patients Pharmaceutical Preparations Pharmacogenomics Pharmacotherapy Piperazines Placebos Process Production Proteins Proteomics Reactive Oxygen Species Recovery Regimen Reperfusion Therapy Resolution Safety Signal Pathway Simulate Staining method Stains Stroke Symptoms Techniques Technology Testing Therapeutic Therapeutic Agents Therapeutic Embolization Time Tissues United States Food and Drug Administration Veterans Vietnam World War II care burden cell injury design drug testing efficacy trial excitotoxicity forest improved insight macromolecule mortality neuroprotection neurosteroids novel oxidative damage phenanthrene pre-clinical pregnane-20-one prevent receptor for advanced glycation endproducts relating to nervous system research study response standard of care trait

项目摘要

DESCRIPTION (provided by applicant): Acute ischemic stroke is now a treatable condition with the thrombolytic, tissue plasminogen activator (tPA). However, tPA is far from being optimal as a therapeutic agent because it produces complete resolution of symptoms in up to 38% of patients, leaving over 60% of patients without full recovery following a stroke. Thus, even with tPA as an FDA-approved therapy, the morbidity rate following a stroke remains high. There is a need for additional treatment modalities that can be used as a monotherapy or in combination with a thrombolytic such as tPA. NMDA antagonists represent such a method to reduce the effects of ischemia-induced excitotoxicity so that the result is improved clinical scores. There are three main objectives of these proposed experiments. First, using a rabbit embolic stroke model, we will directly compare the pharmacological profiles of three novel NMDA antagonists, the uncompetitive NMDA antagonist memantine, which was recently approved for the treatment of Alzheimer's disease because of beneficial effects and a good safety profile, 3-alpha-ol-5-beta-20-one hemisuccinate, a neuroactive steroid that is a negative modulator of the NMDA receptor and (2S*,3R*)-1-(phenanthrene-2-carbonly) piperazine-2,3- dicarboxylic acid a NR2C/NR2D-preferring competitive NMDA receptor antagonist. Second, since tPA therapy is the current standard of care, it is almost certain that NMDA antagonists will be administered in combination with the thrombolytic. We will conduct combination studies to see if tPA and NMDA antagonists produce beneficial effects when administered together. In these studies, we will investigate the relationship between behavior, cell survival (TTC staining) and brain edema. Also, since the most feared complication of tPA therapy is intracerebral hemorrhage, we will investigate whether NMDA antagonists alters this relationship using a rabbit large clot embolic stroke model. As a third objective, we will test the proteomics-derived hypothesis that the AGE-RAGE pathway is involved in neurodegeneration following an embolic stroke. Preliminary evidence shows that aldolase reductase (AR) is increased in cortical tissue following embolic strokes, an increase that is attenuated by memantine administration. We will continue to use state-of-the-art proteomic techniques such as differential in-gel CyDye protein labeling technology to determine changes in protein amount in order to identify signaling pathways that mediate cell damage associated with ischemic stroke and NMDA-induced neuroprotection. These detailed pharmacological and pharmacogenomics studies should provide insight into the possible use of novel NMDA antagonists to treat acute ischemic stroke and supply valuable preclinical information necessary to initiate clinical trials. Moreover, the studies will help us identify new molecular targets for future, more specific therapies for acute ischemic stroke.

描述（由申请人提供）：急性缺血性中风现在是具有溶栓，组织纤溶酶原激活剂（TPA）的可治疗状态。但是，TPA远非最佳作为治疗剂，因为它可以在多达38％的患者中完全解决症状，从而使超过60％的患者在中风后没有完全康复。因此，即使以TPA作为FDA批准的治疗，中风后的发病率仍然很高。需要额外的治疗方式，可以用作单一疗法或与TPA等溶栓结合使用。 NMDA拮抗剂代表了一种减少缺血诱导的兴奋毒性作用的方法，从而改善了临床评分。这些提出的实验有三个主要目标。 First, using a rabbit embolic stroke model, we will directly compare the pharmacological profiles of three novel NMDA antagonists, the uncompetitive NMDA antagonist memantine, which was recently approved for the treatment of Alzheimer's disease because of beneficial effects and a good safety profile, 3-alpha-ol-5-beta-20-one hemisuccinate, a neuroactive steroid that is a negative modulator of the NMDA受体和（2S*，3R*）-1-（苯鞭打2-碳化）哌嗪-2,3-二羧酸a NR2C/NR2C/NR2D优先竞争性NMDA受体拮抗剂。其次，由于TPA治疗是当前的护理标准，因此几乎可以肯定的是，NMDA拮抗剂将与溶栓结合使用。我们将进行组合研究，以查看TPA和NMDA拮抗剂在一起施用时是否产生有益的作用。在这些研究中，我们将研究行为，细胞存活（TTC染色）和脑水肿之间的关系。同样，由于最担心的TPA治疗并发症是脑出血，我们将研究NMDA拮抗剂是否使用兔子大凝块栓塞模型来改变这种关系。作为第三个目标，我们将测试蛋白质组学衍生的假设，即年龄段途径与栓塞性中风后的神经变性有关。初步证据表明，在栓塞性中风后皮质组织中，醛糖酶还原酶（AR）增加，这一增加受到了纪念碑施用的减弱。我们将继续使用最先进的蛋白质组学技术，例如差异内凝胶塞底蛋白标记技术来确定蛋白质量的变化，以识别介导与缺血性中风和NMDA诱导的神经保护作用相关的细胞损伤的信号通路。这些详细的药理学和药物基因组学研究应提供有关新型NMDA拮抗剂治疗急性缺血性中风的可能使用，并提供启动临床试验所需的宝贵临床前信息。此外，这些研究将有助于我们确定未来的新分子靶标的，用于急性缺血性中风的更具体的疗法。