Neuroprotection of pH Sensitive NMDAR Antagonists in Cardiopulmonary Bypass Surge

pH 敏感 NMDAR 拮抗剂在心肺搭桥手术中的神经保护作用

• 批准号: 7220115
• 负责人: SCOTT James MYERS
• 金额: $ 12.58万
• 依托单位: NEUROP, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-01 至 2008-05-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7220115
• 关键词: Affect; Air; Animal Model; Arterial Fatty Streak; Attention Concentration; Blood Platelets; Cardiac; Cardiac Surgery procedures; Cardiopulmonary Bypass; Cerebral Emboli; Cerebral Ischemia; Cerebrovascular Circulation; Cerebrum; Cessation of life; Cognitive; Condition; Coronary Artery Bypass; Embolism; Etiology; Event; Goals; Health Care Costs; Heart; Hospitalization; Impaired cognition; Incidence; Infarction; Injury; Ischemia; Lipids; Medical center; Memory; Modeling; Morbidity - disease rate; Neurocognitive; Neurocognitive Deficit; Neurologic; Numbers; Operative Surgical Procedures; Outcome; Particulate; Patients; Pharmaceutical Preparations; Phase; Prevention; Procedures; Process; Publishing; Range; Rattus; Risk; Speed; Stroke; Tissues; United States National Center for Health Statistics; abstracting; brain tissue; cerebral hypoperfusion; clinically relevant; day; mortality; neuroprotection; novel; older patient; receptor function; remacemide

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.

描述（由申请人提供）：涉及使用体外循环 (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 例手术。此类手术具有显着的脑损伤风险，包括死亡、中风、短暂性脑缺血事件和认知功能障碍。这些不良后果的病因可能是多因素的，且尚未完全了解。然而，人们普遍认为脑灌注不足和栓塞对脑循环造成的缺血性损伤是重要的促成因素。包含血小板聚集体、脂滴、来自动脉粥样硬化斑块的颗粒碎片和气泡的栓子可在心脏手术期间被引入脑微脉管系统中。在开室手术过程中可能会夹带气泡，或者在 CPB 回路内可能会产生大量气泡。尽管已经对十多种药物进行了评估，但没有药物被批准用于预防或治疗使用体外循环心脏手术后的神经或神经认知缺陷。一项已发表的试验涉及 171 名心脏手术患者，使用瑞马塞米（一种低效 NMDAR 拮抗剂），取得了令人鼓舞的结果。这些发现，加上多种 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 拮抗剂减轻涉及 CPB 的心脏手术中脑损伤的潜力提供了强有力的理论依据。我们该项目的学术合作者（杜克医学中心 Mackensen 实验室）建立了一个经过验证的临床相关大鼠体外循环联合脑空气栓塞 (CAE) 后脑损伤模型。暴露于 CPB-CAE 的大鼠会出现梗塞，并表现出神经功能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。这些化合物在健康组织的正常 pH 值下对受体功能影响很小或没有影响，但在局灶性缺血和酸化的情况下有效抑制 NMDAR。 NMDAR阻断剂具有在时间和空间上限制于缺血状况的功效，提供与现有NMDAR拮抗剂所显示的保护相当或优于的保护，但在健康组织中没有NMDAR阻断的不良影响。由于在缺血事件之前或之后不久启动 NMDAR 阻断可提供最大程度的保护，因此 NeurOp 药物特别适合预防心脏手术后的脑损伤，在 CPB 手术之前给药是可行的。该第一阶段项目的目标和唯一目标是确定 NeurOp 的 pH 敏感 NMDAR 拮抗剂是否在由 CAE 叠加 CPB 诱导的大鼠脑损伤模型中发挥神经保护作用。冠状动脉搭桥手术 (CABG) 与心肺搭桥手术 (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 例手术（国家卫生统计中心，2000 年）。接受血运重建手术的患者容易出现一系列神经系统并发症，从中风（发生率 0.4-7.2%）到认知功能障碍（发生率 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费用增加。老年患者尤其面临认知功能障碍的巨大风险，主要影响涉及 CPB 的心脏手术后的注意力、注意力、记忆力和认知处理速度。在这个项目中，有望开发出新药，有一天可能会保护脑组织免受涉及 CPB 的心脏手术期间造成的损伤。