SIRT1在老龄大鼠术后认知功能障碍中的作用及干预研究

As the global acceleration of population aging, the number of elderly people receiving anesthesia and surgery will dramatically increase in China. Postoperative cognitive dysfunction (POCD) is a severe neurological sequela, but the pathophysiological mechanisms and clinical interventions of the complication need to be further elucidated. In the previous experiment we have shown that the protein expression of SIRT1 is significantly upregulated in hippocampi of aged rats after general anesthesia and surgery, while the activity of SIRT is dramatically downregulated. Interestingly, the activator of SIRT1 improves the cognitive function, indicating that the dysfunction of SIRT1 is probably involved in the mechanism of POCD in aged rats. To investigate the role of SIRT1 in POCD of aged rats, this experimental program is performed in aged rats and primary-cultured cells. Furthermore, signaling pathways relevant to dysregulation of SIRT1 in hippocampi of aged rats will be investigated. Combined with the pharmaceutical measurements and anti-virus technology, the designed experiments are conducted to elucidate the role of SIRT1 in POCD of aged rats after general anesthesia and surgery and provide a new prospective for prophylaxis and medication of the neurological complication.

随着中国人口老龄化的加速，越来越多的老龄患者在全身麻醉下接受手术治疗。POCD是老龄患者术后严重的神经并发症，目前关于其发病机制及临床防治措施有待于进一步研究。申请者预实验结果显示，全麻术后老龄大鼠海马SIRT1表达升高，但活性降低；而SIRT1激活剂则可减轻全麻术后老龄大鼠POCD。这提示，SIRT1功能异常可能参与了全麻术后POCD的发病机制。本项目拟从整体动物及体外共培养的神经元-胶质细胞细胞水平，探讨SIRT1在全麻术后老龄大鼠POCD中作用机制，并确定参与调节SIRT1的信号通路；结合药物干预措施及逆转录病毒技术，进一步阐释老龄大鼠POCD病理生理机制，为预防和治疗这种神经并发症提供新的思路。

中国已经进入老龄社会，人口老龄化给我们带来巨大的挑战；随着医学的进步和人们生活质量诉求的增加，越来越来的老年患者接受麻醉手术，据推测到2050年，接受全麻手术患者中约50%是65岁以上的老龄患者；约有40%老龄患者在接受全麻手术治疗后出现认知功能障碍，而这将严重影响患者术后生活质量，并增加致残率及致死率，给当前的医疗、社会服务等方面产生了莫大的压力，故近年来这一领域吸引了很多临床医生及学者的注意力。本课题拟从动物及细胞水平，检测全麻术后SIRT1活性、蛋白表达的变化及SIRT1可能作用底物的表达变化同时通过观察过表达及激活SIRT1对老龄大鼠全麻术后长期认知功能的影响。本项目发现，SIRT1在脑内神经元和小胶质细胞内随着年龄的增加表达降低；在七氟烷麻醉+脾切除模型后，SIRT1表达和活性进一步降低。在神经元内，SIRT1表达降低，导致tau乙酰化；而在小胶质细胞内SIRT1降低，则导致DNMT1和NF-κB上调, 激活小胶质细胞，导致促炎因子释放增加。而使用SIRT1激活白藜芦醇预处理后，tau乙酰化水平减低，小胶质细胞激活减少，促炎因子释放减少, 减轻认知功能损伤。本研究揭示了SIRT1在老龄大鼠POCD中发病机制，干预SIRT1有望成为防治老年患者POCD的可行措施。