Maresin1/GSK-3β炎症消退通路对七氟烷致发育期认知障碍的保护作用及机制研究

Synaptic injury leading to cognitive impairment is a serious sequelae of sevoflurane anesthesia in neonates and infants, the mechanism remains unclear and there are no preventive measures in clinic. Recent studies have indicated that neuroinflammation is closely related to sevoflurane-induced development neurotoxicity, applicant’s preliminary experiment also supported that sevoflurane caused a significant increase in inflammatory cytokines in neonatal mice. Act as “stop signals” for inflammatory diseases, pro-resolving mediator Maresin1 could inhibit inflammation effectively and protect the nervous system against invasion. Applicant’s preliminary experiment found that GSK-3β was involved in the anti-inflammatory actions of Maresin1. Therefore, we hypothesize that Maresin1 could ameliorate sevoflurane induced developmental cognitive impairment through Akt/GSK-3β/NF-κB signaling pathway. With the techniques of behavioral tests, western blot, electrophysiology, molecular biology and so on, this study would confirm the advantaged effect of Maresin1 on synaptic injury and cognitive impairment induced by sevoflurane, mainly explore the mechanism of Maresin1 to protect nerves in developing brains. We expect to find out a specific target to prevent the neurotoxicity of sevoflurane in children.

突触损伤导致认知障碍是新生儿及婴幼儿接受七氟烷麻醉的严重后遗症，其机制尚未明确故临床上缺乏预防措施。研究证实神经炎症与七氟烷致发育期神经损伤密切相关，申请者前期实验亦显示七氟烷引起新生小鼠炎症因子显著升高。作为多种炎症疾病的“炎症刹车信号”，促炎症消退介质Maresin1可有效抑制炎症和保护神经系统抵御侵害。申请者前期研究发现GSK-3β参与Maresin1调节神经炎症。我们推断Maresin1通过调控Akt/GSK-3β/NF-κB信号通路改善七氟烷导致的发育期认知障碍。本项目拟通过建立七氟烷致新生鼠和原代海马神经损伤模型，借助行为学、蛋白印迹、电生理、分子生物等技术，明确Maresin1对七氟烷致新生鼠突触损伤及认知功能障碍的改善作用，重点探讨Maresin1调控Akt/GSK-3β/NF-κB信号通路发挥神经保护作用的机制，为防治七氟烷引起的儿童神经损伤提供有效的治疗靶点和思路。