Neuroprotection with serpins during cardiac surgery

描述(申请人提供)：成人和儿童在心脏手术期间和之后都会发生脑损伤。它可以采取局部或全局性神经侮辱的形式，如中风或编舞运动障碍。或者，它可以表现为认知和运动技能的普遍下降。抑肽酶是一种SERPIN(丝氨酸蛋白酶抑制剂)，可以减少体外循环(CPB)后的出血。心脏外科文献的一项广泛的荟萃分析得出结论，抑肽酶也降低了体外循环后中风的发生率，尽管最近一份有影响力的报告表明，脑损伤的风险增加。体外循环期间抑肽酶直接作用于神经元和神经血管的机制仍未得到很大程度的研究，尽管先前的工作已经证明抑肽酶对内皮功能有保护作用。此外，最近在神经科学文献中应用细胞培养模型的报告表明，一些蛇可能通过抑制兴奋性毒性而起到神经保护作用。这项拟议的研究将检验抑肽酶在体外循环中具有神经保护作用的假设。将使用幼猪模型，暴露在不同程度的流量减少到已知会导致脑损伤的程度。术后存活4天，可以通过盲人观察者的行为评估和盲人神经病理学家确定的有意义的组织学来评估脑损伤的功能证据。血管完整性将用活体显微镜进行研究，这种显微镜可以直接观察大脑微循环。大脑供氧的充分性将通过近红外光谱分析进行监测。几种剂量水平的抑肽酶将被用来确定最佳剂量。这项研究的第二部分将检验抑肽酶具有神经保护作用的机制之一是通过抑制兴奋性毒性这一假设。将采用神经细胞培养模型。不同剂量的抑肽酶将与之前被证明具有神经保护作用的其他蛇类进行比较。可能在心脏手术中应用的新型蛇类也将通过细胞培养模型进行研究。在第三阶段的研究中，将在CPB的整个动物模型中详细研究被发现具有保护作用的蛇毒。最后阶段将研究抑肽酶提供的血管保护机制。这项拟议的研究有可能降低接受心脏手术的儿童和成人的脑损伤风险。

DESCRIPTION (provided by applicant): Brain injury occurs during and after cardiac surgery in both adults and children. It can take the form of either a focal or global neurological insult such as stroke or choreoathetosis. Alternatively it can manifest itself as a generalized decline in cognitive and motor skills. Aprotinin, a "SERPIN" (serine protease inhibitor), reduces bleeding after cardiopulmonary bypass (CPB). An extensive metaanalysis of the cardiac surgery literature concluded that aprotinin also decreases the incidence of stroke after CPB though a recent influential report suggests an increased risk of brain injury. Direct neuronal and neurovascular mechanisms of action of aprotinin during CPB remain largely unexplored though previous work has demonstrated protection of endothelial function by aprotinin. Furthermore recent reports in the neuroscience literature applying cell culture models suggest that some serpins may be neuroprotective through inhibition of excitotoxicity. The proposed study will test the hypothesis that aprotinin is neuroprotective in the setting of CPB. A juvenile piglet model will be employed with exposure to various degrees of flow reduction to a degree known to cause brain injury. Survival for 4 days postoperatively allows assessment of functional evidence of brain injury through behavioral assessment by a blinded observer as well as meaningful histology determined by a blinded neuropathologist. Vascular integrity will be studied with intravital microscopy which allows direct observation of the cerebral microcirculation. Adequacy of cerebral oxygen delivery will be monitored by near infrared spectroscopy. Several dosage levels of aprotinin will be employed to determine optimal dose. The second component of the study will test the hypothesis that one mechanism by which aprotinin is neuroprotective is through inhibition of excitotoxicity. Neuronal cell culture models will be employed. Aprotinin at various dosages will be compared with other serpins which have previously been demonstrated to be neuroprotective. Novel serpins which may have an application in cardiac surgery will also be studied with the cell culture model. Serpins which are found to be protective will be studied in detail in the whole animal model of CPB in the third phase of the study. The final phase will study mechanisms of vascular protection afforded by aprotinin. The proposed study has the potential to reduce the risk of brain injury in children and adults undergoing heart surgery.