Xia Tianjiao, Cui Yin, Chu Shuaishuai, Song Jia, Qian Yue, Ma Zhengliang, Gu Xiaoping
Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical Department of Nanjing University, 321 Zhong Shan Road, Nanjing, Jiangsu 210008, PR China.
Brain Res. 2016 Mar 1;1634:12-20. doi: 10.1016/j.brainres.2015.10.036. Epub 2015 Oct 28.
Sleep plays an important role in memory processing. However, its role in anesthesia-induced cognitive dysfunction was not revealed. Our study sought to investigate the connection between the cognition decline and sleep-wake rhythm disorders after long-term isoflurane anesthesia in mice. Also, we examined the effect of exogenous melatonin pretreatment on both cognitive function and circadian rhythm. Furthermore, we discussed whether NR2B (N-methyl-D-aspartate receptor 2B subunit)-CREB (cAMP-response element binding protein) signaling pathway was involved in this course.
2-month-old male C57/BL-6J mice were submitted to long-term anesthesia using 1% isoflurane from CT (Circadian Time) 14 to CT20. Melatonin pretreatment were conducted before anesthesia for 7 Days. Intellicage for mice and Mini-Mitter were applied to monitor spatial memory and gross motor activity which can reflect cognition and sleep-wake rhythm. Messenger RNA and protein expression of right hippocampus NR2B and CREB were examined by RT-PCR and Western blot.
6h isoflurane anesthesia led to impaired spatial memory from Day 3 to Day 10 in mice accompanied by the disruption of sleep-wake rhythm. Meanwhile, the hippocampus CREB and NR2B expression declined in step. Melatonin pretreatment ameliorated disturbed sleep-wake cycle, improved isoflurane-induced cognitive dysfunction, and reversed the down-regulation of CREB and NR2B expression.
Our data demonstrate that sleep-wake rhythm is involved in the isoflurane-induced cognition impairment and pretreatment of melatonin has a positive effect on circadian normalization and cognition reversal. Also, NR2B-CREB signaling pathway has a critical role in this process. This study provides us a new strategy for anesthesia-induced cognitive dysfunction therapy.
睡眠在记忆处理中起着重要作用。然而，其在麻醉诱导的认知功能障碍中的作用尚未明确。我们的研究旨在探讨小鼠长期异氟烷麻醉后认知功能下降与睡眠-觉醒节律紊乱之间的联系。此外，我们研究了外源性褪黑素预处理对认知功能和昼夜节律的影响。此外，我们还讨论了NR2B（N-甲基-D-天冬氨酸受体2B亚基）-CREB（环磷酸腺苷反应元件结合蛋白）信号通路是否参与了这一过程。
2月龄雄性C57/BL-6J小鼠于昼夜时间（CT）14至CT20期间使用1%异氟烷进行长期麻醉。在麻醉前7天进行褪黑素预处理。使用小鼠智能笼和Mini-Mitter监测空间记忆和总体运动活动，这些可以反映认知和睡眠-觉醒节律。通过RT-PCR和蛋白质免疫印迹法检测右海马NR2B和CREB的信使核糖核酸和蛋白质表达。
6小时的异氟烷麻醉导致小鼠在第3天至第10天空间记忆受损，同时伴有睡眠-觉醒节律紊乱。与此同时，海马CREB和NR2B表达同步下降。褪黑素预处理改善了睡眠-觉醒周期紊乱，改善了异氟烷诱导的认知功能障碍，并逆转了CREB和NR2B表达的下调。
我们的数据表明，睡眠-觉醒节律参与了异氟烷诱导的认知损伤，褪黑素预处理对昼夜节律正常化和认知功能恢复具有积极作用。此外，NR2B-CREB信号通路在这一过程中起关键作用。本研究为麻醉诱导的认知功能障碍治疗提供了一种新策略。
