Neurological Impact of Cardiopulmonary Bypass Surgery

描述(申请人提供)：体外循环(CPB)手术对神经系统的长期影响可能是深远的。最近的研究表明，42%的CPB患者在手术后五年的评估中观察到显著的认知能力下降。这是一个重大的生物医学问题，因为美国每年进行的心脏搭桥手术超过50万例。CPB导致认知功能下降的根本原因是有争议的，也不是很清楚。这项应用的总体目标是描述CPB相关损伤的机制，并评估CPB后长期认知障碍的治疗策略。我们的初步发现表明，在CPB的大鼠模型中，复杂认知任务的表现至少会受到5-6个月的损害。Aim#1下的研究将在这种可复制的动物模型中表征CPB对行为的影响，并将建立评估CPB后长期认知功能障碍的基准。目的#2将研究CPB诱导损伤的三种细胞机制：神经炎症、抑制的成人神经发生和选择性神经元丢失。初步数据表明，CPB后至少6个月内，海马区会出现持续的局部神经炎症。初步研究结果还表明，在神经炎症区，成人的神经发生显著减少。这些发现将在Aim#2中得到证实和推广，它刺激了一种假设，即海马体持续的神经炎症会抑制成人的神经发生，进而产生长期的认知障碍。目的#3将通过评估抗炎治疗对CPB的神经遗传学和认知后果的保护作用来检验这一概念。在目标1项下建立的行为损害基准将在这些研究中用作认知功能的衡量标准。据推测，阻断CPB的炎症反应将减弱对神经发生的抑制，改善认知结果。总之，建议的研究将：1)建立一种评估CPB啮齿动物恢复模型中长期认知缺陷的方法；2)表征CPB有害影响的基本细胞机制；以及3)评估阻断和/或逆转CPB相关认知下降的特定治疗策略。这一结果将扩大我们对CPB相关损伤机制的基本理解，并将评估一种限制CPB后认知功能下降的合理候选疗法。

DESCRIPTION (provided by applicant): The long-term neurological impact of cardio-pulmonary bypass (CPB) surgery can be profound. Recent studies indicate that significant cognitive decline is observed in 42% of CPB-patients when assessed five years after the procedure. This is a substantial biomedical problem because over 500,000 cardiac bypass procedures are performed each year in the United States. The underlying causes of CPB-induced cognitive decline are controversial and not well understood. The overall goal of this application is to characterize mechanisms of CPB-related injury and to evaluate a therapeutic strategy for treating long-term cognitive deficits after CPB. Our preliminary findings indicate that performance on a complex cognitive task is impaired for at least 5-6 months in a rat model of CPB. Studies under Aim #1 will characterize the behavioral impact of CPB in this replicable animal model, and will establish benchmarks for assessing long-term cognitive dysfunction after CPB. Aim #2 will examine three cellular mechanisms proposed to underlie CPB-induced injury: neuroinflammation, suppressed adult neurogenesis, and selective neuronal loss. Preliminary data indicate that sustained, localized neuroinflammation occurs in the hippocampus for at least 6 months after CPB. The preliminary findings also indicate that a substantial decrease in adult neurogenesis occurs in the area of neuroinflammation. These findings, which will be confirmed and extended under Aim #2, spur the hypothesis that sustained neuroinflammation in the hippocampus suppresses adult neurogenesis, which in turn produces long-term cognitive impairment. Aim #3 will test this concept by evaluating the protective effects of anti-inflammatory therapy on the neurogenetic and cognitive consequences of CPB. The benchmarks for behavioral impairment, established under Aim #1, will be used as a measure of cognitive function in these studies. It is hypothesized that blocking the inflammatory response to CPB will attenuate the suppression of neurogenesis and improve cognitive outcome. Together, the proposed studies will: 1) establish a means for assessing long-term cognitive deficits in a rodent recovery model of CPB, 2) characterize fundamental cellular mechanisms that underlie the deleterious effects of CPB, and 3) evaluate a specific therapeutic strategy for blocking and/or reversing cognitive decline associated with CPB. The results will expand our fundamental understanding of the mechanisms underlying CPB-related injury and will assess a rational candidate therapy for limiting cognitive decline after CPB.