Novel NMDA Antagonists to Treat Stroke

描述（由申请人提供）： 急性缺血性中风现在是一种可治疗的条件与血栓溶解，组织纤溶酶原激活剂（tPA）。然而，tPA作为治疗剂远非最佳，因为它在高达38%的患者中产生症状的完全消退，使得超过60%的患者在中风后没有完全恢复。因此，即使tPA作为FDA批准的疗法，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溶栓药物如tPA联合使用。NMDA拮抗剂代表了这样一种方法，以减少缺血诱导的兴奋性毒性的影响，从而改善临床评分的结果。 这些拟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的NMDA拮抗剂的药理学特征，非竞争性NMDA拮抗剂美金刚，其最近因有益作用和良好的安全性特征而被批准用于治疗阿尔茨海默病，3-α-醇-5-β-20-酮半琥珀酸酯，一种神经活性类固醇，其是NMDA受体的负调节剂，和（2S*，3R*）-1-（菲-2-羰基）哌嗪-2，3-二羧酸是一种NR 2C/NR 2D优先的竞争性NMDA受体拮抗剂。其次，由于tPA治疗是目前的标准治疗，几乎可以肯定的是，NMDA拮抗剂将与溶栓药物联合给药。我们将进行联合研究，以观察tPA和NMDA拮抗剂联合给药时是否产生有益作用。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治疗最可怕的并发症是脑内出血，我们将研究是否NMDA拮抗剂改变这种关系使用兔大血块栓塞中风模型。作为第三个目标，我们将测试蛋白质组学衍生的假设，即AGE-E2通路参与栓塞性卒中后的神经退行性变。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，美金刚胺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，如差异凝胶CyDye蛋白标记技术，以确定蛋白质量的变化，以确定介导与缺血性卒中和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提供洞察新的NMDA拮抗剂治疗急性缺血性卒中的可能用途，并提供启动临床试验所需的有价值的临床前信息。此外，这些研究将帮助我们确定新的分子靶点，用于未来更特异性的急性缺血性卒中治疗。

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.