手术创伤对APP/PS1双转基因鼠长时程认知功能损害的影响及炎性因子在认知功能损害中的作用

Elderly patients undergoing surgical intervention often suffer from postoperative cognitive dysfunction (POCD), a condition characterized by the progressive deterioration of cognitive function following surgery. Several theories have been advanced to explain the mechanisms of POCD. It remains unclear whether its occurrence is directly related to surgical trauma. A substantial body of evidence indicates that significantly elevated expression of pro-inflammatory cytokines, particularly in the hippocampus, results in impairments in long-term potentiation (LTP) and performance deficits in hippocampal-mediated cognitive tests. In the present study, we investigated the effects of partial hepatectomy on spatial learning and memory and hippocampal pro-inflammatory cytokines in APP/ PS1 transgenic mice and wild type mice. Both APP/ PS1 transgenic mice and wild type mice were randomly divided into a total of fourteen groups: control, anesthesia alone, operation group, sham operation group,JWH-133+operation group,RU486+operation group and MSC2032964A+operation group. Control animals received sterile saline to control for effects of injection stress. The anesthesia alone group received 1.5% to 2% isoflurane with intubation and mechanical ventilation. The operation group performed partial hepatectomy under general anesthesia.JWH-133+operation group RU486+operation group and MSC2032964A+ operation group were received with JWH-133,RU486 or MSC2032964A except operation. Cognitive function was assessed in a reversal-learning version of the Morris water maze (MWM) before and after surgery. Mice were sacrificed on postoperative days 7, 37, and 97 after spatial working tests. Hippocampal tissues of half of the mice in each group were quickly dissected and stored at -70 C until they were assayed for central cytokines. The remaining animals in each group were killed and perfused transcardially for immunohistochemistry. Hippocampal pro-inflammatory cytokines IL-1β, IL-6 and TNF-α and glial cell activation markers glial fibrillary acidic protein (GFAP) and S100β were measured at each time point. β- amyloid, phosphorylated tau, Synapsins and apoptosis protein were also measured at same time point.

术后认知功能障碍(POCD)确切发病机制尚不明确。研究多集中于POCD临床危险因素的流行病学分析和短时程POCD的研究。本课题以神经系统老化的APP/ PS1双转基因小鼠作为研究对象，率先提出长时程POCD可能是在神经系统老化基础上, 由麻醉、手术等外界因素诱发或加重了认知功能损害的假设。以肝部分切除术作为手术创伤模型，探讨实验鼠认知功能损害，创新性的使用分子影像学技术在体研究海马区炎性因子表达，利用IL-1?受体阻滞剂和大麻素明确炎性因子在手术创伤引起认知功能损害中的作用。探讨手术创伤对血脑屏障通透性的影响以及过多糖皮质激素在术后认知功能损害中的作用。研究炎性因子信号通路TLR-ASK1-P38 MAPK在抑制中枢神经系统炎症反应中的作用以及手术创伤与认知功能相关突触蛋白表达的影响，寻找预防和治疗POCD的新途径。

术后认知功能障碍是老年患者术后常见的一种并发症，POCD确切的发病机制尚不明确。老年是目前唯一明确的POCD的危险因素。老年增强了老年患者中枢神经系统炎症反应。急性或者慢性应激刺激可以引起认知功能损害，手术创伤对患者无疑是最大的应激刺激。糖皮质激素作为应激刺激重要的内源性应激激素，对中枢神经系统功能有许多影响，包括学习和记忆功能，在应激过程中产生过量糖皮质激素会损害认知功能。.我们研究发现与成年鼠相比，麻醉手术创伤引起老年鼠海马区炎性因子（IL-1、IL-6）表达增多，小胶质细胞激活增强，而抗炎因子IL-4表达下降。侧脑室注射外源性IL-4能够抑止炎性反应和小胶质细胞过度激活，改善了实验鼠空间学习记忆能力。.老年鼠和成年鼠给予连续14天的慢性刺激，然后实施肝部分切除术。研究发现，与单纯手术创伤相比，14天的慢性刺激加剧了手术创伤引起的海马区炎性因子表达和小胶质细胞过度表达，而脑源性神经营养因子表达降低。而给予糖皮质激素受体阻滞剂RU486阻滞了易化作用。明确了糖皮质激素的作用。这项研究提示减少手术创伤或者采用微创手术能够减少术后认知功能障碍的发生。.年龄相关的抗炎因子IL-4加剧了手术创伤引起的海马区炎症反应和实验鼠空间学习记忆能力损害。外源性的IL-4通过抑制小胶质细胞过度激活，增强CD200表达和BDNF表达，从而抑止海马区炎症反应和改善空间学习记忆能力。慢性不可预知的刺激易化了手术创伤引起的海马区炎性因子表达和空间学习记忆能力损害。应激刺激引起的糖皮质激素通过调整小胶质细胞功能异化中枢神经系统炎症反应。