Novel NMDA Antagonists to Treat Stroke

治疗中风的新型 NMDA 拮抗剂

• 批准号: 8397583
• 负责人: Bhaumik B Patel
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 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/8397583
• 关键词: Acute; Advanced Glycosylation End Products; Age; Agonist; Aldehyde-Lyases; Alteplase; Alzheimer' 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; public health relevance; receptor for advanced glycation endproducts; relating to nervous system; research study; response; standard of care; trait

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可以通过溶栓组织纤溶酶原激活剂 (tPA) 来治疗。然而，tPA 作为治疗剂还远未达到最佳状态，因为它可以使高达 38% 的患者症状完全缓解，从而使超过 60% 的患者在中风后无法完全康复。因此，即使 tPA 作为 FDA 批准的治疗方法，中风后的发病率仍然很高。需要可用作单一疗法或与溶栓剂（例如 tPA）组合使用的额外治疗方式。 NMDA 拮抗剂代表了一种减少缺血引起的兴奋性毒性影响的方法，从而改善临床评分。 这些提议的实验有三个主要目标。首先，使用兔栓塞性中风模型，我们将直接比较三种新型 NMDA 拮抗剂的药理学特征，即无竞争性的 NMDA 拮抗剂美金刚，由于有益效果和良好的安全性，最近被批准用于治疗阿尔茨海默病，3- α-ol-5-β-20-one 半琥珀酸酯，一种神经活性类固醇，是 NMDA 受体的负调节剂(2S*,3R*)-1-(菲-2-碳基)哌嗪-2,3-二甲酸是一种 NR2C/NR2D 优先的竞争性 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 NMDA 拮抗剂将与溶栓剂联合使用。我们将进行联合研究，看看 tPA 和 NMDA 拮抗剂一起服用时是否会产生有益的作用。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。此外，由于 tPA 治疗最令人担心的并发症是脑出血，我们将使用兔大血栓栓塞性中风模型研究 NMDA 拮抗剂是否改变这种关系。作为第三个目标，我们将测试蛋白质组学衍生的假设，即 AGE-RAGE 通路参与栓塞性中风后的神经退行性变。初步证据表明，栓塞性中风后皮质组织中的醛缩酶还原酶（AR）增加，美金刚给药可减弱这种增加。我们将继续使用最先进的蛋白质组学技术，例如差异凝胶内 CyDye 蛋白质标记技术来确定蛋白质含量的变化，从而确定介导与缺血性中风和 NMDA 诱导的神经保护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有助于深入了解新型 NMDA 拮抗剂治疗急性缺血性中风的可能性，并为启动临床试验提供必要的有价值的临床前信息。此外，这些研究将帮助我们确定未来更具体的急性缺血性中风治疗的新分子靶点。