不同剂量依达拉奉对防治七氟醚诱导术后认知功能障碍的研究

Effects of different doses of edaravone on prevention of postoperative cognitive dysfunction induced by sevoflurane

目的探究不同剂量依达拉奉对七氟醚诱导全麻术后认知功能障碍(POCD)的防治作用。方法老龄雄性Balb/c小鼠48只,随机均分为对照组(Con组)、七氟醚组(Sev组)、七氟醚+依达拉奉低剂量组(Sev+Eda-L组,6 mg·kg^(-1))、七氟醚+依达拉奉高剂量组(Sev+Eda-H组,12 mg·kg^(-1))。采用多次麻醉/手术构建老龄小鼠POCD模型,期间给予不同剂量依达拉奉注射液。通过Morris水迷宫实验检测小鼠学习与记忆能力,采用相应试剂盒检测氧化/抗氧化因子、炎性细胞因子,采用免疫荧光检测海马中Iba1表达,采用Western blot检测海马组织中TLR4/NF-κB信号通路的蛋白表达。结果与Con组相比,Sev组小鼠逃避潜伏期显著较长,且穿越平台次数、在第Ⅰ象限停留的时间显著较少/短(P<0.05)。与Sev组相比,Sev+Eda-L组小鼠Morris水迷宫指标无明显变化(P>0.05)。与Sev组相比,Sev+Eda-L组小鼠海马中超氧歧化酶(SOD)活力及丙二醛(MDA)、Iba1、TLR4、p-NF-κB、NLRP3、IL-6、IL-1β、TNF-α水平均无显著变化(P>0.05)。而Sev+Eda-H组小鼠Morris水迷宫指标被显著正向调节(P<0.05)。与Sev组相比,Sev+Eda-H组小鼠海马中SOD活力显著增加(P<0.05),MDA、Iba1、TLR4、p-NF-κB、NLRP3、IL-6、IL-1β、TNF-α水平均显著降低(P<0.05)。结论6 mg·kg^(-1)依达拉奉对氧自由基的清除能力较弱,因此无法发挥防治POCD的作用,但当剂量达到12 mg·kg^(-1)时,依达拉奉能够有效清除氧自由基,抑制炎症信号通路,提高小鼠学习与记忆能力。

Objective To investigate the preventive and therapeutic effects of different doses of edaravone on postoperative cognitive dysfunction(POCD)after sevoflurane induced general anesthesia.Methods Forty-eight aged male Balb/c mice were randomly divided into the control group(Con group),the sevoflurane group(Sev group),the sevoflurane+edaravone low-dose group(Sev+Eda-L group,6 mg·kg^(-1))and the sevoflurane+edaravone high-dose group(Sev+Eda-H group,12 mg·kg^(-1)).POCD model of aged mice was established by multiple anesthesia/operations,during which edaravone injection was given in different doses.Morris water maze test was used to detect the learning and memory ability of mice;oxidative/antioxidant factors and inflammatory cytokines were detected by corresponding kits;Iba1 expression in hippocampus was detected by immunofluorescence;the protein expression of TLR4/NF-κB signaling pathway in hippocampus was detected by Western blot.Results Compared with the Con group,the escape latency was significantly longer in the Sev group,and the number of platforms crossing and the residence time in the first quadrant were significantly less/shorter in the Sev group(P<0.05).Compared with the Sev group,there was no significant change in the Morris water maze index of the Sev+Eda-L group(P>0.05).Compared with the Sev group,the superoxide dismutase(SOD)activity and malonic dialdehyde(MDA),Iba1,TLR4,p-NF-κB,NLRP3,IL-6,IL-1β,TNF-αexpression levels in hippocampus of the Sev+Eda-L group had no significant change(P>0.05).However,compared with the Sev group,the Morris water maze index of the Sev+Eda-H group had significantly positive regulation(P<0.05).Compared with the Sev group,the SOD activity in the hippocampus of the Sev+Eda-H group was significantly increased(P<0.05),while the levels of MDA,Iba1,TLR4,p-NF-κB,NLRP3,IL-6,IL-1βand TNF-αin the Sev+Eda-H group were significantly decreased(P<0.05).Conclusion Edaravone of 6 mg·kg^(-1)has a weak ability to scavenge oxygen free radicals,so it cannot play the role of POCD prevention and treatment.However,when the dose of edaravone reaches 12 mg·kg^(-1),it can effectively scavenge oxygen free radicals,inhibit the inflammatory signaling pathway,improve the learning and memory ability of mice.