术后疼痛介导的海马神经可塑性改变诱发老年POCD—IGF-2基因失调的作用及机制研究

项目名称： 术后疼痛介导的海马神经可塑性改变诱发老年POCD—IGF-2基因失调的作用及机制研究

项目编号： No.81471106

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 戴茹萍

作者单位： 中南大学

项目金额： 70万元

中文摘要： 术后认知功能障碍（POCD）是严重影响老年病人术后生活质量的常见并发症。研究表明术后疼痛可诱发老年POCD，但其作用机制尚不清楚。课题组预实验发现剖腹探查手术后疼痛导致老年、而非年轻大鼠的认知功能下降以及海马神经纤维萎缩；手术后年轻、而非老年大鼠海马胰岛素样生长因子（IGF）-2表达上调。本课题遂假设IGF-2代偿性上调是年轻大鼠抵消术后疼痛导致的海马神经纤维萎缩和认知功能下降的重要机制；老年大鼠缺乏此代偿机制而诱发POCD。为此，本课题拟首先明确神经可塑性改变在术后疼痛诱发老年POCD中的作用；通过观察IGF-2信号通路的表达以及干预海马IGF-2信号对术后疼痛诱发老年POCD的影响，明确IGF-2调控失代偿在老年POCD产生中的作用；最后探讨DNA甲基化在老年和年轻大鼠术后IGF-2差异性表达的调控作用。本课题的实施将为POCD的产生机制提供新理论，为临床上防治POCD提供新思路。

中文关键词： 术后认知功能障碍；神经可塑性；术后疼痛；胰岛素样生长因子-2；DNA甲基化

英文摘要： Postoperative dysfunction (POCD) is a common postoperative complication which severely affects the life quality of the aging people. More and more evidence has shown that postoperative pain contributes to the development of aging POCD. However, the underlying mechanism is still elusive. Our preliminary study confirmed that postoperative pain after laparotomy decreased learning and memory in the aging but not young rats as determined by Morris Water Maze experiments. The decreased spatial learning and memory was concomittant with the dendritic retraction and decreased expression of MAP-2 and PSD-95 in the aging but not young rats. These findings suggest that pain-related hippocampal neuroplasticity mediates the development of aging POCD. More interestingly, we observed that in response to postoperative pain, hippocampal IGF-2 gene and protein expression were upregulated in the young, but not aging rats. Given that hippocampal IGF-2 could promote dendritic spine maturation, neurogenesis and improve cognitive function, the present study hypothesized that upregulation of IGF-2 in response to pain plays a critical role in the fact that young rats do not develop cognitive impairment after surgery. However, in the aging rats, the compensatory mechanism have lost due to epigenetic disability and therefore resulted in the nerve fibers retraction, and subsequently the development of POCD. In order to test the hypothesis, we firstly assess whether neuroplasticity plays a critical role in the development of aging POCD. Furthermore, the present study will examine the role of IGF-2 signaling in the nerve fibers' retraction and cognitive impairment. Finally, the study will explore the role of DNA methylation in the differential expression of IGF-2 in the aging and young rats after laparotomy. The project will provide a noverl mechanism of aging POCD, and may have potential clinical application for the treatment of POCD since IGF-2 is a nutrient which can taken orally.

英文关键词： postoperative cognitive dysfunction;neuroplasticity;postoperative pain;insulin-like growth factor-2;DNA methylation