脑铁代谢在POCD中枢神经炎症机制中的作用

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 focused on inhaled anesthetics and inflammatory factors after surgery. However, the mechanism of how to regular neuroinflammation to treat impaired cognitive function. These gaps of knowledge block prevention and treatment of diseases involve neuroinflammation including POCD. We have established the animal model of surgery under local anesthesia to avoid the effect of general anesthesia. We found the impaired cognition, neuroinflammation and increased permeability of blood brain barrier after surgery in previously study. Also the treatment of mice with LPS resulted in deficits in cognitive performance in the Morris water maze without changing locomotor activity, which were ameliorated by pretreatment with DFO. DFO prevented LPS-induced microglial activation and elevations of IL-1β and TNF-α levels in the hippocampus. Moreover, DFO prevented LPS-induced increases of MDA and SOD levels in the hippocampus. DFO also significantly blocked LPS-induced iron accumulation and altered expression of proteins related to iron metabolism in the hippocampus. Besides these findings, our preliminary data suggests that the free radical scavenger edaravone could protect surgery plus lipopolysaccharide administration induced POCD. It might relate to its anti-oxidative stress and anti-inflammatory effects. Recent studies confirmed that p38MAPK and downstream NFκB regulates the neuroinflammation. So we draw the hypothesis that: regulates the iron metabolism in central nervous system attenuates neuroinflammatory cognitive dysfunction via p38MAPK pathway. We ask the proposal here to determine the mechanism of how iron metabolism in central nervous system effect neuroinflammatory cognitive dysfunction via p38MAPK pathway to treat POCD.

术后认知功能障碍(POCD)增加了患者术后的并发症和死亡率，目前对其研究主要集中于吸入麻醉药和手术炎症的影响，但是具体机制不清楚。我们前期研究发现手术导致中枢炎症、POCD，并且发现调节脑铁代谢可以改善中枢炎症及其导致的认知功能障碍，发现自由基清除剂依达拉奉可以改善POCD、减轻中枢炎症。通过前期研究及文献复习，我们推测脑铁代谢异常导致中枢炎症反应的机制是：游离铁离子通过Fenton反应增加脑内的活性氧（ROS），ROS激活p38MAPK及其下游信号通路，从而导致中枢炎症的发生发展（炎症因子释放、小胶质细胞激活等）。然而，由于ROS 还存在其他下游信号通路，脑铁代谢异常是否确切通过p38MAPK信号通路诱发中枢炎症，尚难以定论。因此，我们提请本研究项目，通过离体、在体及临床研究验证我们所提出的假说，明确p38MAPK信号通路在脑铁代谢异常致中枢炎症反应中的确切分子机制。

术后认知功能障碍(POCD)增加了患者术后的并发症和死亡率，目前对其研究主要集中于吸入麻醉药和手术炎症的影响，但是具体机制不清楚。我们前期研究发现手术导致中枢炎症、POCD，并且发现调节脑铁代谢可以改善中枢炎症及其导致的认知功能障碍，发现自由基清除剂依达拉奉可以改善POCD、减轻中枢炎症。通过前期研究及文献复习，我们推测脑铁代谢异常导致中枢炎症反应的机制是：游离铁离子通过Fenton反应增加脑内的活性氧（ROS），ROS激活p38MAPK及其下游信号通路，从而导致中枢炎症的发生发展。.在研究中，我们发现维生素C预处理可能通过调节氧化应激和炎症反应来保护小鼠免受脂多糖诱导的认知障碍，POCD大鼠海马区胰岛素信号通路发生了紊乱，POCD大鼠的糖代谢也出现了异常，氧化应激引起的线粒体异常在脂多糖(LPS)诱导的记忆损伤的病理生理中起重要作用，新型的线粒体靶向抗氧化剂Elamipretide (SS-31)对炎症和氧化应激导致认知障碍有很好的保护作用，elamipretide不仅提供了对线粒体功能障碍的保护作用，而且促进了脑源性神经营养因子(BDNF)信号的调节，麻醉后新生大鼠认知功能障碍与海马组织内果蝇相关蛋白3(TRB3)表达增加及p-Akt ( Ser473) 的降低有关，老年大鼠每天1次重复异丙酚处理可促进NFκB和NLRP3的激活炎症小体，导致认知功能障碍和神经炎症。Bay11-7082预处理不仅抑制了NFκB/NLRP3炎症小体的激活，而且减轻了每日异丙酚处理老年大鼠的神经元损伤和认知功能障碍。.本项目同时与其他自然基金项目资助了脑缺血再灌注损伤的研究，结果首先发现棉籽油处理通过减少小胶质和星形激活和炎症减轻缺血性中风损伤,棉籽油可以成为预防缺血性中风的新策略。我们还研究了转运蛋白(translocator protein, TSPO 18kda)在创伤后应激障碍(PTSD)的发病机制。通过这一系列研究，实现了探索并确定调控脑铁代谢、ROS释放改善POCD的作用和机制，发现p38MAPK信号通路在调控脑铁代谢、ROS 释放调控中枢炎症性 POCD 中的分子机制。