大麻二酚通过调节昼夜节律改善大鼠全麻术后的睡眠障碍

doi:10.12122/j.issn.1673-4254.2025.04.09

南方医科大学学报 ›› 2025, Vol. 45 ›› Issue (4): 744-750.doi: 10.12122/j.issn.1673-4254.2025.04.09

• • 上一篇

大麻二酚通过调节昼夜节律改善大鼠全麻术后的睡眠障碍

吴新顺¹^,²(), 李劲草³, 刘影³, 邱仁洪³, 王恒林², 薛瑞³, 张扬³, 李硕³, 范琼尹³, 董华进³, 张有志³, 曹江北⁴()

^1.中国人民解放军医学院，北京 100853
^2.中国人民解放军总医院第六医学中心麻醉科，北京 100048
^3.军事医学研究院，北京 100850
^4.中国人民解放军总医院第一医学中心麻醉科，北京 100853

收稿日期:2024-12-30 出版日期:2025-04-20 发布日期:2025-04-28
通讯作者: 曹江北 E-mail:185501229@qq.com;caojiangbei@301hospital.com.cn
作者简介:吴新顺，在读硕士研究生，E-mail: 185501229@qq.com
基金资助:
国家自然科学基金(82271213);国家重点新药开发计划(2017ZX09309020)

Cannabidiol regulates circadian rhythm to improve sleep disorders following general anesthesia in rats

Xinshun WU¹^,²(), Jingcao LI³, Ying LIU³, Renhong QIU³, Henglin WANG², Rui XYE³, Yang ZHANG³, Shuo LI³, Qiongyin FAN³, Huajin DONG³, Youzhi ZHANG³, Jiangbei CAO⁴()

^1.Medical School of Chinese PLA, Beijing 100853, China
^2.Department of Anesthesiology, Sixth Medical Center of Chinese PLA General Hospital, Beijing 100048, China
^3.Academy of Military Medical Siences, Beijing 100850, China
^4.Department of Anesthesiology, First Medical Center of Chinese PLA General Hospital, Beijing 100853, China

Received:2024-12-30 Online:2025-04-20 Published:2025-04-28
Contact: Jiangbei CAO E-mail:185501229@qq.com;caojiangbei@301hospital.com.cn
Supported by:
National Natural Science Foundation of China(82271213)

摘要/Abstract

摘要：

目的通过建立丙泊酚诱导的节律紊乱型睡眠障碍大鼠模型，利用无线生理信号遥测系统评估大麻二酚（CBD）对全身麻醉后睡眠节律紊乱的调节作用，并探讨其可能机制。方法实验选取雄性SD大鼠，建立丙泊酚诱导的节律紊乱型睡眠障碍大鼠模型，并将大鼠随机分为4组（n=6）：对照组（Sal组）、丙泊酚组（Pro组）、CBD治疗组（Pro+CBD组）和地西泮阳性对照组（Pro+DZP组）。利用无线遥测系统采集各组大鼠的脑电（EEG）、肌电（EMG）及体温等生理信号。分离大鼠下丘脑组织，检测（PER2、CRY2、BMAL1、CLOCK、SIRT1和GSK3β）等关键时钟蛋白的表达水平及血清中氧化应激指标MDA和SOD表达水平。结果与Sal组相比，CBD增加了大鼠在黑暗期（20∶00~6∶00）的睡眠时间（P<0.01），尤其在凌晨4∶00~6∶00表现出差异（P<0.05）；Pro大鼠在明暗过渡期间（18∶00~24∶00）的慢波睡眠（SWS）总时间和睡眠片段数增加（P<0.05），且睡眠-觉醒的转换次数增加（P<0.05）。与Pro组相比，CBD组的SWS总时间明显减少（P<0.01），且CBD抑制了从SWS向活跃清醒状态的转变（P<0.05）。阳性对照药物地西泮（DZP）的作用与CBD相似，但其对睡眠-觉醒转换的影响不明显。在夜间时段（24∶00~08∶00），CBD增加了SWS的总时间、睡眠片段数量及平均持续时间（P<0.05），且增强了睡眠-觉醒的转换次数（P<0.05）。相较之下，DZP虽然增加了SWS的睡眠片段数（P<0.05），但对平均持续时间影响无统计学意义。此外，与Sal组相比，丙泊酚麻醉引起BMAL1、CLOCK和SIRT1蛋白表达的升高（P<0.05），而CBD能够抑制这种异常增高（P<0.05）。另一方面，丙泊酚麻醉导致PER2、CRY2和GSK3β蛋白表达的降低（P<0.05），而CBD则能有效逆转这种异常下调（P<0.05）。丙泊酚麻醉导致氧化还原状态的分子MDA升高、SOD降低（P<0.05）。CBD能够减少MDA的产生，使SOD水平恢复（P<0.05）。结论 CBD可能通过干预下丘脑核心时钟蛋白的表达，改善麻醉后睡眠节律紊乱型障碍大鼠的睡眠结构和生物节律，为临床围手术期睡眠障碍的干预提供了新的潜在治疗策略。

关键词: 术后睡眠障碍, 丙泊酚, 大麻二酚, 时钟蛋白

Abstract:

Objective To assess the regulatory effect of cannabidiol (CBD) on circadian rhythm sleep disorders following general anesthesia and explore its potential mechanism in a rat model of propofol-induced rhythm sleep disorder. Methods An electrode was embedded in the skull for cortical EEG recording in 24 male SD rats, which were randomized into control, propofol, CBD treatment, and diazepam treatment groups (n=6). Eight days later, a single dose of propofol (10 mg/kg) was injected via the tail vein with anesthesia maintenance for 3 h in the latter 3 groups, and daily treatment with saline, CBD or diazepam was administered via gavage; the control rats received only saline injection. A wireless system was used for collecting EEG, EMG, and body temperature data within 72 h after propofol injection. After data collection, blood samples and hypothalamic tissue samples were collected for determining serum levels of oxidative stress markers and hypothalamic expressions of the key clock proteins. Results Compared with the control rats, the rats with CBD treatment showed significantly increased sleep time at night (20:00-6:00), especially during the time period of 4:00-6:00 am. Compared with the rats in propofol group, which had prolonged SWS time and increased sleep episodes during 18:00-24:00 and sleep-wake transitions, the CBD-treated rats exhibited a significant reduction of SWS time and fewer SWS-to-active-awake transitions with increased SWS aspects and sleep-wake transitions at night (24:00-08:00). Diazepam treatment produced similar effect to CBD but with a weaker effect on sleep-wake transitions. Propofol caused significant changes in protein expressions and redox state, which were effectively reversed by CBD treatment. Conclusion CBD can improve sleep structure and circadian rhythm in rats with propofol-induced sleep disorder possibly by regulating hypothalamic expressions of the key circadian clock proteins, suggesting a new treatment option for perioperative sleep disorders.

Key words: postoperative sleep disturbance, propofol, cannabidiol, circadian clock proteins

吴新顺, 李劲草, 刘影, 邱仁洪, 王恒林, 薛瑞, 张扬, 李硕, 范琼尹, 董华进, 张有志, 曹江北. 大麻二酚通过调节昼夜节律改善大鼠全麻术后的睡眠障碍[J]. 南方医科大学学报, 2025, 45(4): 744-750.

Xinshun WU, Jingcao LI, Ying LIU, Renhong QIU, Henglin WANG, Rui XYE, Yang ZHANG, Shuo LI, Qiongyin FAN, Huajin DONG, Youzhi ZHANG, Jiangbei CAO. Cannabidiol regulates circadian rhythm to improve sleep disorders following general anesthesia in rats[J]. Journal of Southern Medical University, 2025, 45(4): 744-750.

图/表 5

图 1 CBD对正常大鼠睡眠的调节作用

Fig.1 Regulatory effects of CBD on sleep in normal rats. A: Timeline of experiments. B: Sleep duration of the rats in the day time (8:00-18:00) and the night time (20:00-6:00). C: Sleep duration at different time points. D: Average body temperature per hour. CBD: Cannabidiol; IG: Intragastric administration. *P<0.05, **P<0.01 vs baseline.

图 2 CBD对异丙酚麻醉后18:00~24:00期间睡眠结构的调节作用

Fig.2 Regulatory effects of CBD on sleep architecture from 18:00 to 24:00 in rats following propofol anesthesia. A: Experimental flowchart. B: Duration of states in different pre-treatment groups. C: Mean duration of each state. D: State occurrence count. E: Number of entries into each state. Pro: Propofol; DZP: Diazepam; CBD: Cannabidiol; W: Wake; AW: Active wake; PS: Paradoxical sleep; SWS: Slow wave sleep. *P<0.05, **P<0.01.

图 3 CBD对异丙酚麻醉后24:00~08:00期间睡眠结构的调节作用

Fig.3 Regulatory effects of CBD on sleep architecture from 24:00 to 08:00 in rats following propofol anesthesia. A: Experimental flowchart. B: Duration of states in different pre-treatment groups. C: Mean duration of each state. D: State occurrence count. E: Number of entries into each state. *P<0.05, **P<0.01.

图 4 各组大鼠节律基因蛋白表达水平的对比

Fig.4 Effects of CBD on expression levels of circadian clock proteins in rats following propofol anesthesia. A-F: Protein expressions of BMAL1, CLOCK, PER2, CRY2, GSK3β and SIRT1 in rat hypothalamus. The expression level of protein was quantified and presented as a ratio relative to GAPDH. *P<0.05, **P<0.01, ***P<0.001.

图 5 各组大鼠CB1蛋白表达水平及血清中MDA和SOD水平的对比

Fig.5 Regulatory effects of CBD on protein expression of CB1 (A) and serum levels of MDA (B) and SOD (C) of the rats. The expression level of protein was quantified and presented as a ratio relative to GAPDH. *P<0.05.

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大麻二酚通过调节昼夜节律改善大鼠全麻术后的睡眠障碍

Cannabidiol regulates circadian rhythm to improve sleep disorders following general anesthesia in rats

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