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以用溶栓的组织型纤溶酶原激活剂(TPA)治疗的疾病。然而，tPA作为一种治疗剂远非理想，因为它能使高达38%的患者的症状完全消失，使超过60%的患者在中风后无法完全康复。因此，即使将tPA作为FDA批准的治疗方法，中风后的发病率仍然很高。需要可作为单一疗法或与tPA等溶栓剂联合使用的附加治疗方式。NMDA拮抗剂代表了这样一种方法，可以减少缺血诱导的兴奋性毒性的影响，从而改善临床评分。这些拟议的实验有三个主要目标。首先，利用兔血栓卒中模型，我们将直接比较三种新的NMDA拮抗剂的药理学特征，即最近被批准用于治疗阿尔茨海默病的非竞争性NMDA拮抗剂美金刚，它具有良好的疗效和良好的安全性，3-α-醇-5-β-20-酮半琥珀酸半琥珀酸酯，一种神经活性类固醇，NMDA受体的负调节剂，以及(2S*，3R*)-1-(菲-2-碳基)哌嗪-2，3-二羧酸，NR2C/NR2D-偏好竞争性NMDA受体拮抗剂。其次，由于tPA治疗是目前的护理标准，几乎可以肯定的是，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拮抗剂在一起使用时是否会产生有益的效果。在这些研究中，我们将调查行为、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出血，我们将使用兔大块血栓栓塞性卒中模型来研究NMDA拮抗剂是否改变了这种关系。作为第三个目标，我们将检验蛋白质组学派生的假说，即年龄-愤怒通路与栓塞性中风后的神经退行性变有关。初步证据表明，在栓塞性中风后，皮质组织中的醛缩酶还原酶(AR)增加，这种增加可被美金刚治疗缓解。我们将继续使用最先进的蛋白质组学技术，如差异凝胶内CyDye蛋白质标记技术来确定蛋白质数量的变化，以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将为可能使用新型NMDA拮抗剂治疗急性缺血性中风提供洞察力，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新的分子靶点，为未来治疗急性缺血性中风提供更具体的治疗方法。 公共卫生相关性： 中风的频率随着年龄的增长而增加，在第二次世界大战、朝鲜战争和越南退伍军人的大群体中，中风现在是一个主要的医学问题。我们研究的目的是确定预防或最小化中风损伤的药物疗法。这应该有助于减少人类痛苦方面的损失，以及护理大量中风患者的巨大经济负担。如果我们能够减少脑血管疾病造成的发病率和死亡率，那么开发特定治疗方法的努力将很容易得到证明。

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. PUBLIC HEALTH RELEVANCE: Stroke frequency increases with age, and in the large groups of World War II, Korean War and Viet Nam veterans, stroke is now a major medical problem. The purpose of our study is to identify pharmacologic therapies that prevent or minimize stroke injury. This should help reduce the losses in terms of human suffering and the enormous financial burdens of caring for large numbers of patients who suffer from strokes. If we are able to reduce morbidity and mortality caused by cerebrovascular diseases, the effort to develop specific therapy will be readily justified.