右美托咪定对异氟烷麻醉引起的老年小鼠认知功能障碍保护作用及机制研究

Protective effect and mechanism of dexmedetomidine on isoflurane anesthesia-induced cognitive impairment in old mice

目的:研究右美托咪定对异氟烷麻醉后老年小鼠认知功能的影响,并探讨其内在的分子机制。方法:45只C57BL/6J小鼠被随机分为三组,对照组小鼠仅吸氧4 h,模型组小鼠吸入氧气+1.5%异氟烷气体4 h,治疗组小鼠腹腔注射15μg/kg的右美托咪定后吸入氧气+1.5%异氟烷气体4 h。使用Morris水迷宫和矿场实验比较三组小鼠认知功能,TUNEL染色法检测小鼠海马区神经元凋亡情况,免疫印迹法检测小鼠海马区BCL2-Associated X的蛋白质(Bax)和B淋巴细胞瘤-2基因(Bcl-2)蛋白表达情况。结果:三组小鼠麻醉期间血气分析各项生理指标(血浆pH,PO_(2)和PCO_(2))均在正常范围内波动,组间比较无统计学差异(均P>0.05)。与对照组小鼠相比,模型组小鼠每天平均逃逸潜伏期均显著延长(P<0.05),而治疗组小鼠每天逃逸潜伏期均较模型组显著缩短(P<0.05)。空间探索实验结果显示:与对照组小鼠比较,模型组小鼠在目的象限活动时间和穿越平台次数均显著降低(均P<0.05),而治疗组小鼠在目的象限活动时间和穿越平台次数均较模型组显著增加(均P<0.05)。与对照组小鼠相比,模型组小鼠海马区神经元凋亡数目和Bax蛋白表达水平均显著增加,经右美托咪定治疗后均显著降低(均P<0.05);模型组小鼠海马区Bcl-2蛋白表达水平显著低于对照组和治疗组小鼠(均P<0.05)。结论:右美托咪定可显著改善异氟烷麻醉引起的老年小鼠认知功能障碍,其机制与通过Bax/Bcl-2轴调控的小鼠海马区神经元凋亡有关。

Objective:To study the effect of dexmedetomidine on cognitive function in aged mice after isoflurane anesthesia,and to explore its underlying molecular mechanism.Methods:Forty-five C57BL/6J mice were randomly divided into 3 groups.The mice in the control group were only inhaled with oxygen for 4 hours.The mice in the model group were inhaled with oxygen and 1.5%isoflurane gas for 4 hours.The mice in the treatment group were intraperitoneally injected with 15μg/kg dexmedetomidine,and then oxygen and 1.5%isoflurane gas was administered for 4 hours.The cognitive function of the three groups was compared by using the Morris water maze and the mining field test.TUNEL staining was used to detect the apoptosis of neurons in the hippocampus of the mice.Western blot was used to detect the protein expressions of Bax and Bcl-2 in the hippocampus of the mice.Results:During the period of anesthesia in the three groups,the physiological indicators of blood gas analysis(plasma pH,PO_(2) and PCO_(2))all fluctuated within the normal range,and there was no significant difference between the groups(all P>0.05).Compared with the control group,the average daily escape latency in the model group was significantly prolonged,while the daily escape latency in the treatment group was significantly shorter than that in the model group(all P<0.05).The results of the space exploration experiment showed that compared with the control group,the activity time and the number of crossing the platform in the model group were significantly reduced,while the activity time and the number of crossing the platform in the treatment group were significantly increased(all P<0.05).Compared with the control group,the number of apoptotic neurons and the expression of Bax protein in the hippocampus of the mice in the model group were significantly increased,and were significantly decreased after dexmedetomidine treatment(all P<0.05).The expression level of Bcl-2 protein in the hippocampus was significantly lower than that in the control and treatment groups(all P<0.05).Conclusion:Dexmedetomidine can significantly improve isoflurane anesthesia-induced cognitive dysfunction in aged mice,and its mechanism is related to neuronal apoptosis in the hippocampus of mice regulated by the Bax/Bcl-2 axis.