中枢神经炎症反应在术后认知功能障碍病理生理中的机制研究

Postoperative cognitive dysfunction or decline (POCD) is an increasingly recognized phenomenon after major surgery and is associated with impairments in daily functioning and increased morbidity and mortality. Previous studies have identified advanced age as the major risk factor for long-term POCD. Neuroinflammation has been reported as a part of neuropathogenesis of cognitive impairment in some diseases. Several studies suggested that surgery or trauma induces neuroinflammation and cognitive dysfunction which implies neuroinflammation is one of possible neuropathogenesis of POCD. The accident of neuroinflammation was not declined in the patients undergone surgery with general anesthesia although it is common accepted that stress is the major risk factor for that. This phenomenon suggests that there are some other risk factors for neuroinflammation even general anesthesia depress the stress. The neuropathogenesis of how neuroinflammation impairs cognitive function remains largely unknown and this gap of knowledge blocks prevention and treatment of POCD. In this study, by the animal experiments, brain slices and cultured sells, using the methods of animal behavior detection, epigenetics, electrophysiology, neuron cells and glial cells co-culturing and so on, we want to investigate the important role of neuropathogenesis during the development of POCD.The aims of this study are: find and determine the etiopathogenisis of neuroinflammation; determine the neuropathogenesis of how neuroinflammation impairs cognitive function; find and determine the prevention and/or treatment for neuroinflammation and cognitive decline.We hope that the results could be eventually provide the basis for the prevention and treatment of clinical POCD.

术后认知功能障碍(POCD)是最常见的术后并发症之一。POCD的发生可增加患者术后并发症和死亡率，增加家庭及社会的医疗支出，已引起各国的高度重视。但由于POCD发病原因复杂，且尚无统一定论，目前临床POCD并未得到有效的防治。多项研究发现手术和创伤可以导致中枢神经炎症，并认为中枢神经炎症可能是导致POCD的重要原因之一。但中枢神经炎症发生途径，以及炎症发生后如何影响认知功能尚不清楚。本研究拟通过动物模型、脑片及培养细胞三个层面，利用动物行为学检测、表观遗传学、电生理学、神经元细胞与胶质细胞共培养、免疫组化及分子生物学等实验方法对中枢神经炎症在POCD发生过程中的重要作用进行研究。目的在于：1. 寻找并确定术后中枢神经炎症发生的原因；2. 研究中枢神经炎症发生后影响认知功能途径；3. 寻找合理并切实的预防和/或治疗术后中枢神经炎症的方法。最终为临床POCD的防治提供依据。

术后认知功能障碍(POCD)是老年患者最常见的术后并发症之一。POCD可增加患者术后并发症和死亡率，增加家庭及社会的医疗支出，目前仍是相关领域重点和热点关注问题之一。本项目立足于中枢神经炎症在POCD病理生理中的机制作用，从诱发中枢炎症的因素，到中枢炎症抑致中枢神经元突触形成和突触可塑性的相关机制，以及抗炎策略对预防和/或治疗术后中枢神经炎症从而改善POCD等多方面展开了详尽的研究。本研究团队在此资金的资助下，不仅进一步完善了相关动物实验的平台，在理论研究方面也获得了丰富的研究成果。研究成果如下：1）手术应激可以导致老龄小鼠认知功能障碍而心理应激则无明显影响，AKT/同同TOR信号通路参与了此过程；2）腹腔注射LPS100μg/kg/d 复合左肾切除术建立大鼠动物模型，结果显示该处理可以激活前脑皮层小胶质细胞并导致海马及前脑皮层的神经元损伤，从而最终导致大鼠的认知功能下降。其机制与抑制COX-2蛋白水平及增强p-AKT-GSK3β相关；3）TSPO配体PK11195可以对脂多糖诱导脑损伤产生脑保护作用，其机制可能与抑制脑内COX-2，抑制海马Aβ、BACE-1、IDE含量，以及增加海马内孕酮水平相关；4）老年小鼠术后认知功能障碍发生机制与中枢神经系统NMDAR-NF-κB - NOS信号通路相关；5)去铁胺可以减轻脑室注射LPS致小鼠中枢神经炎症及学习记忆障碍。去铁胺可以抑制脑室注射LPS引起的海马IL-1β及TNFα水平升高，同时去铁胺可以下调LPS导致的caspase-3,修饰后GSK3β水平活性，以及MDA、SOD水平升高。6）利用脑室注射LPS建立认知功能障碍的小鼠动物模型，腹腔注射对乙酰基酚（APAP）可以改善模型小鼠的认知功能。其机制可能与APAP抑制LPS诱发的海马神经区神经炎性反应及星型胶质细胞活化相关。这些研究成果对阐明POCD的发生机制提供了十分有利的证据，由此而设计的围术期POCD防治策略目前正应用于围术期患者并期待着良好的应用效果。