Neuroprotection of pH Sensitive NMDAR Antagonists in Cardiopulmonary Bypass Surge

描述（由申请人提供）：涉及使用心肺转流（CPB）的心脏手术是世界上最常见的外科手术之一，2000年仅在美国就进行了超过500，000例。此类手术具有显著的脑损伤风险，包括死亡、中风、短暂性缺血事件和认知功能障碍。这些不良结局的病因可能是多因素的，尚未完全了解。然而，人们普遍认为，脑灌注不足和脑循环栓塞造成的缺血性损伤是重要的促成因素。在心脏手术期间，可将包含血小板聚集体、脂滴、来自动脉粥样硬化斑块的微粒碎片和气泡的栓塞引入脑微血管系统中。在开放腔室手术期间可能会夹带气泡，或者在CPB回路内产生大量气泡。虽然已经评估了十几种药物，但没有药物被批准用于预防或治疗使用CPB的心脏手术后的神经或神经认知缺陷。一项涉及171名心脏手术患者的低效力NMDAR拮抗剂瑞马西胺的已发表试验产生了令人鼓舞的结果。这些发现以及不同NMDAR拮抗剂在各种脑缺血动物模型中的强大神经保护作用，为研究NMDAR拮抗剂减轻CPB心脏手术中脑损伤的潜力提供了有力的依据。本项目的学术合作者（Mackensen实验室，杜克医学中心）已建立了经验证的临床相关的CPB合并脑空气栓塞（CAE）后脑损伤大鼠模型。暴露于CPB-CAE的大鼠发生梗死，并表现出神经和神经认知功能下降。我们正在开发具有pH依赖性效力的新型NMDAR拮抗剂。这些化合物在正常pH下对健康组织中的受体功能几乎没有影响或没有影响，但在局灶性缺血和酸化的情况下有效地抑制NMDAR。具有在时间和空间上局限于缺血性病症的功效的NMDAR阻断剂提供与现有NMDAR拮抗剂所显示的保护相当或上级的保护，但在健康组织中没有NMDAR阻断的不希望的作用。由于NMDAR阻断在缺血事件之前或之后不久开始时提供最大保护，因此NeurOp药物特别适合用于预防心脏手术后的脑损伤，其中在CPB手术之前给予药物是可行的。该I期项目的目标和唯一目的是确定NeurOp的pH敏感性NMDAR拮抗剂是否在CPB叠加CAE诱导的脑损伤大鼠模型中发挥神经保护作用。冠状动脉旁路手术（CABG）和心肺转流（CPB）是世界上最常见的外科手术之一，2000年仅在美国就进行了超过500，000例（国家卫生统计中心，2000年）。接受血运重建手术的患者容易发生一系列神经系统并发症，从卒中（发生率为0.4-7.2%）到认知功能障碍（发生率为25-79%），导致住院时间延长、发病率和死亡率增加以及总体医疗保健费用增加。老年患者尤其存在认知功能障碍的重大风险，主要影响CPB心脏手术后的注意力、集中力、记忆力和认知处理速度。在这个项目中，有希望的新药可能有一天会保护脑组织免受CPB心脏手术造成的损伤。

DESCRIPTION (provided by applicant): Heart operations involving the use of cardiopulmonary bypass (CPB) are among the most common surgical procedures in the world, with over 500,000 performed in the U.S. alone in 2000. Such procedures carry a significant risk of cerebral injury including death, stroke, transient ischemic events and cognitive dysfunction. The etiology of these adverse outcomes is likely multifactorial and not fully understood. However, it is widely accepted that cerebral hypoperfusion and ischemic damage inflicted by emboli to the cerebral circulation are significant contributing factors. Emboli comprising platelet aggregates, lipid droplets, particulate debris from atherosclerotic plaques and air bubbles may be introduced into the cerebral microvasculature during heart surgery. Air bubbles may be entrained during open chamber procedures or generated in large numbers within the CPB circuit. Although over a dozen agents have been evaluated, no drug is approved for the prevention or treatment of neurological or neurocognitive deficit after heart surgery using CPB. A published trial involving 171 cardiac surgery patients of remacemide, a low potency NMDAR antagonist, yielded encouraging results. These findings, together with the robust neuroprotective effects of diverse NMDAR antagonists in various animal models of cerebral ischemia, provide a strong rationale to investigate the potential for NMDAR antagonism to mitigate cerebral injury in heart surgery involving CPB. Our academic collaborators for this project, (Mackensen lab, Duke Medical Center) have an established, validated, clinically relevant, rat model of cerebral injury after CPB combined with cerebral air emboli (CAE). Rats exposed to CPB-CAE suffer infarcts and demonstrate diminished neurological and neurocognitive function. We are developing novel NMDAR antagonists having pH dependent potency. These compounds have little or no effect on receptor function at normal pH in healthy tissue, but effectively inhibit NMDAR in the context of focal ischemia and acidification. NMDAR blockers having efficacy that is temporally and spatially restricted to ischemic conditions, offer protection that is comparable or superior to that shown by prior NMDAR antagonists, but without unwanted effects of NMDAR blockade in healthy tissue. Since NMDAR blockade provides maximal protection when initiated prior to, or very soon after an ischemic event, NeurOp drugs are particularly well suited for the prevention of cerebral injury after cardiac surgery, where it is feasible to administer drug prior to the CPB surgery. The goal and sole AIM of this phase 1 project is to determine whether NeurOp's pH sensitive NMDAR antagonists exert neuroprotective effects in a rat model of cerebral injury induced by CAE superimposed upon CPB. Coronary artery bypass surgery (CABG) with cardiopulmonary bypass (CPB) is one of the most common surgical procedures in the world, with over 500,000 performed in the U.S. alone in 2000 (National Center for Health Statistics, 2000). Patients undergoing revascularization procedures are prone to a spectrum of neurological complications ranging from stroke (0.4-7.2% incidence) to cognitive dysfunction (25-79% incidence) resulting in prolonged hospitalization, increased morbidity and mortality as well as increased overall health care costs. Elderly patients in particular are at substantial risk for cognitive dysfunction, primarily affecting attention, concentration, memory, and speed of cognitive processing after cardiac surgery involving CPB. In this project promising new drugs that may one day protect brain tissue from damage caused during cardiac procedures involving CPB.