血管性痴呆大鼠脑内时钟基因在不同发病时程中的改变及山茱萸环烯醚萜苷的调节作用

doi:10.20047/j.issn1673-7210.2023.08.02

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摘要目的观察血管性痴呆大鼠脑内时钟基因在不同发病时程中的改变及山茱萸环烯醚萜苷（CIG）的调节作用。方法选取45只SPF级雄性SD大鼠，6~8周，体重150~180 g，选取15只作为假手术组，其余采用双侧颈总动脉结扎（2VO）术制作慢性脑缺血模型。造模成功后采用随机数字表法将假手术动物分为3组，造模动物分为6组，每组5只。具体为造模1个月组（Sham组、2VO组、2VO+CIG60组、2VO+CIG120组、2VO+丁苯酞组）；造模1.5个月组（Sham组、2VO组）；造模3个月组（Sham组、2VO组）。造模6 h后2VO+CIG60组灌胃CIG 60 mg/（kg·d）、2VO+CIG120组灌胃CIG 120 mg/（kg·d）、2VO+丁苯酞组灌胃丁苯酞100 mg/（kg·d），Sham组与2VO组灌胃等量的生理盐水。造模后1、1.5、3个月时，取大鼠的下丘脑和中脑检测时钟基因CRY1、PER1、PER2、NPAS2 mRNA的水平，观察时钟基因的改变情况。结果在下丘脑中，与Sham组比较，造模1个月2VO组PER2 mRNA降低（P＜0.01）；造模1.5个月2VO组时钟基因PER2 mRNA、NPAS2 mRNA升高（P＜0.05或P＜0.01）。在中脑中，与Sham组比较，造模1个月2VO组CRY1 mRNA、PER1 mRNA升高（P＜0.05或P＜0.01）；造模3个月2VO组PER2 mRNA升高（P＜0.05）。在下丘脑中，与Sham组比较，2VO组PER2 mRNA降低（P＜0.01）；与2VO组比较，2VO+CIG60组NPAS2 mRNA升高，2VO+CIG120组PER1 mRNA降低（P＜0.05）。在中脑中，与Sham组比较，2VO组CRY1 mRNA、PER1 mRNA升高（P＜0.05或P＜0.01）；与2VO组比较，2VO+CIG120组CRY1 mRNA降低（P＜0.01）。结论血管性痴呆模型大鼠的下丘脑和中脑中时钟基因表达紊乱，引起调节昼夜节律的反馈环破坏，而CIG能纠正下丘脑和中脑时钟基因紊乱表达现象。

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	郑层层张丽李雅莉李林张兰杨翠翠

关键词 ：血管性痴呆, 时钟基因, 昼夜节律, 山茱萸环烯醚萜苷

Abstract：Objective To observe the changes of clock genes in the brain of vascular dementia rats in different time courses and the regulatory effect of cornel iridoid glycoside (CIG)． Methods A total of 45 SPF male SD rats, 6-8 weeks old, weighing 150-180 g were selected, and 15 rats were selected as Sham operation group, the rest were established by 2-vessel occlusion (2VO) to establish the chronic cerebral ischemia model. After successful modeling, the Sham operation animals were divided into three groups, and the model animals were divided into six groups by random number table method, with five animals in each group. The specific groups were modeling 1 month group (Sham group, 2VO group, 2VO+CIG60 group, 2VO+CIG120 group, 2VO+ Butylphthalide group); modeling 1.5 months group (Sham group, 2VO group); modeling 3 months group (Sham group, 2VO group). After six hours of modeling, CIG 60 mg/(kg·d) was gavaged in 2VO+CIG60 group, CIG 120 mg/(kg·d) was gavaged in 2VO+CIG120 group, Butylphthalide 100 mg/(kg·d) was gavaged in 2VO+Butylphthalide group, and Sham group and 2VO group were gavage with the same amount of normal saline. At 1, 1.5, and 3 months after modeling, the hypothalamus and midbrain of rats were taken to detect the levels of clock genes CRY1, PER1, PER2, and NPAS2 mRNA, the changes of clock genes were observed. Results In hypothalamus, compared with Sham group, PER2 mRNA in 2VO group was decreased at 1 month after modeling (P＜0.01); clock gene PER2 mRNA and NPAS2 mRNA in 2VO group were increased at 1.5 months after modeling (P＜0.05 or P＜0.01). In midbrain, compared with Sham group, CRY1 mRNA and PER1 mRNA in 2VO group were higher at 1 month after modeling (P＜0.05 or P＜0.01); PER2 mRNA in 2VO group was increased at 3 months of modeling (P＜0.05). In hypothalamus, compared with Sham group, PER2 mRNA in 2VO group was decreased (P＜0.01); compared with 2VO group, NPAS2 mRNA in 2VO+CIG60 group was increased, PER1 mRNA in 2VO+CIG120 group was decreased (P＜0.05). In midbrain, compared with Sham group, CRY1 mRNA and PER1 mRNA in 2VO group were increased (P＜0.05 or P＜0.01); compared with 2VO group, CRY1 mRNA in 2VO+CIG120 group was decreased (P＜0.01). Conclusion Disordered expression of clock genes in the hypothalamus and midbrain of vascular dementia model rats causes disruption of the feedback loop that regulates circadian rhythm, and CIG can correct the disordered expression of clock genes in the hypothalamus and midbrain.

Key words： Vascular dementia Clock genes Circadian rhythm Cornel iridoid glycoside

基金资助:国家自然科学基金资助项目（82074040）；
首都卫生发展科研专项项目（首发2020-4-2017）；
北京市医院管理中心“青苗”计划专项项目（QML20210806）；
北京市医院管理中心“登峰”计划专项项目（DFL20190803）。

通讯作者: 杨翠翠（1985-），女，博士，副教授；研究方向：神经退行性疾病机制及药理研究、新药研发。张兰（1972-），女，博士，教授；研究方向：临床药学、临床药理及神经药理。

作者简介: 郑层层（1996-），女，首都医科大学宣武医院2021级药理学专业在读博士研究生；研究方向：神经药理学。

引用本文:

郑层层张丽李雅莉李林张兰杨翠翠. 血管性痴呆大鼠脑内时钟基因在不同发病时程中的改变及山茱萸环烯醚萜苷的调节作用[J]. 中国医药导报, 2023, 20(8): 12-16.
ZHENG Cengceng ZHANG Li LI Yali LI Lin ZHANG Lan YANG Cuicui. Changes of clock genes in the brain of vascular dementia rats in different time courses and the regulatory effect of cornel iridoid glycoside. 中国医药导报, 2023, 20(8): 12-16.

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