柴胡疏肝散改善肝气郁结型大鼠抑郁症的机制：基于microPET/CT方法

王伟; 陈英茂; 王玉来; 郭蓉娟; 王璐绮; 丛俊婕; 贺立娟

doi:10.12122/j.issn.1674-4500.2023.04.01

柴胡疏肝散改善肝气郁结型大鼠抑郁症的机制：基于microPET/CT方法

doi: 10.12122/j.issn.1674-4500.2023.04.01

1.
北京中医药大学东方医院康复科，北京 100078
2.
中国人民解放军总医院核医学科，北京 100853
3.
北京中医药大学东方医院脑病科，北京 100078
4.
北京中医药大学东方医院心血管科，北京 100078

基金项目:

国家自然科学基金 30973706

详细信息

作者简介:
王伟，在读硕士研究生，E-mail: 1132671945@qq.com

通讯作者:
贺立娟，博士，副主任医师，E-mail: ljhebj@126.com

计量
- 文章访问数: 310
- HTML全文浏览量: 214
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- 被引次数: 0
出版历程
- 收稿日期: 2023-04-25
- 网络出版日期: 2023-07-18
- 刊出日期: 2023-07-20

Mechanism of Chaihu Shugan powder in improving depression rats with liver-qi stagnation based on microPET/CT

1.
Department of Rehabilitation, Dongfang Hospital, Beijing University of Chinese Medicine, Beijing 100078, China
2.
Department of Nuclear Medicine, Chinese PLA General Hospital, Beijing 100853, China
3.
Department of Brain Disease, Dongfang Hospital, Beijing University of Chinese Medicine, Beijing 100078, China
4.
Department of Cardiovascular, Dongfang Hospital, Beijing University of Chinese Medicine, Beijing 100078, China

Funds:

National Nature Science Foundation of China 30973706

摘要

摘要: 目的观察柴胡疏肝散对肝气郁结型抑郁症大鼠行为改善，并探索其临床疗效机制是否是通过改善脑葡萄糖代谢发挥抗抑郁作用。方法雄性Wistar大鼠40只，按体质量匹配原则随机分为对照组、模型组和柴胡疏肝散高、低剂量组，10只/组，运用慢性束缚应激结合孤养法建立肝气郁结型大鼠模型，柴胡疏肝散高、低剂量组分别用1.04 g/mL及0.52 g/mL的浓缩药液灌胃，对照组与模型组用生理盐水灌胃，灌胃从实验开始之日起，1次/d，持续21 d。观察旷场实验和糖水偏好实验变化，使用小型正电子发射断层显像与CT摄影融合术观察大鼠感兴趣脑区的脑葡萄糖代谢变化。结果行为学提示：与对照组相比，模型组大鼠糖水偏好程度下降（P < 0.05），旷场实验不动时间延长（P < 0.05）。脑代谢提示：模型组代谢增高脑区：双侧延髓、左侧小脑（P < 0.05），代谢减低脑区：双侧胼胝体、双侧M1、双侧M2、左侧纹状体、右侧丘脑、右侧海马、右侧前额叶皮质、右侧扣带皮质、右侧S1、右侧S2、右侧岛叶皮质（P < 0.05）。与模型组相比，高、低剂量组糖水偏好程度增高（P < 0.05），旷场实验不动时间减少（P < 0.05）；低剂量组代谢增高脑区：双侧纹状体、双侧海马、双侧胼胝体、双侧前额叶皮质、左侧下丘、左侧M2、右侧听觉皮质、右侧丘脑、右侧M1、右侧S1、右侧S2、右侧岛叶皮质（P < 0.05），代谢减低脑区：左侧延髓、左侧视觉皮质、左侧小脑（P < 0.05）；高剂量组代谢增高脑区：右侧前额叶皮质（P < 0.05）；其它感兴趣脑区二者的差异无统计学意义（P>0.05）。结论肝气郁结证发病机制为慢性应激结合孤养法降低情绪认知和行为调节相关脑区葡萄糖代谢，使之失代偿，同时使左脑纹状体、小脑脑区发生葡萄糖摄取竞争，柴胡疏肝散可改善肝气郁结型抑郁症大鼠行为，其主要通过改善与情绪认知、行为等相关脑区及改善左脑纹状体、小脑脑区葡萄糖摄取竞争从而发挥抗抑郁效应。
- 抑郁症 /
- 肝气郁结证 /
- 柴胡疏肝散 /
- microPET/CT
Abstract: Objective To investigate the effects of Chaihu Shugan powder on the behavior of rats with liver-qi stagnation depression and to explore the potential antidepressant mechanism of Chaihu Shugan powder through the improvement of brain glucose metabolism. Methods Forty male Wistar rats were randomly divided into control group, model group, low-dose Chaihu Shugan powder group, and high-dose Chaihu Shugan powder group, with 10 rats per group. A rat model of liver-qi stagnation was established by using chronic restraint stress combined with solitary rearing. The high and low dose Chaihu Shugan powder groups were administered 1.04 g/mL and 0.52 g/mL concentrated solutions by gavage, respectively. The control and model groups were treated with normal saline by gavage once daily for 21 days from the beginning of the experiment. Results Behavioral indicators: Compared with the control group, the sucrose preference of the rats in the model group significantly decreased (P < 0.05), and the immobility time in the open field test significantly increased (P < 0.05). Brain metabolism indicators: The brain regions with increased metabolism in the model group were the bilateral medulla oblongata and left cerebellum (P < 0.05), while the brain regions with decreased metabolism included bilateral corpus callosum, bilateral M1, bilateral M2, left striatum, right thalamus, right hippocampus, right prefrontal cortex, right cingulate cortex, right S1, right S2, and right insular cortex (P < 0.05). In comparison with the model group, both high-and low-dose groups showed a significant increase in sucrose preference (P < 0.05) and a significant decrease in immobility time in the open field test (P < 0.05). In the low-dose group, the brain regions with increased metabolism encompassed bilateral striatum, bilateral hippocampus, bilateral corpus callosum, bilateral prefrontal cortex, left inferior colliculus, left M2, right auditory cortex, right thalamus, right M1, right S1, right S2, right insular cortex (P < 0.05), whereas the brain regions with decreased metabolism included left medulla, left visual cortex, and left cerebellum (P < 0.05). The high-dose group displayed increased metabolism in the right prefrontal cortex (P < 0.05). No significant differences were observed in other regions of interest (P>0.05). Conclusion The pathogenesis of liver-qi stagnation syndrome may involve chronic stress combined with isolation, resulting in decreased glucose metabolism in brain regions related to emotional cognition and behavioral regulation, leading to decompensation and concurrent glucose uptake competition in the left striatum and cerebellar brain regions. Chaihu Shugan powder can improve the behavior of rats with liver-qi stagnation depression by exerting its antidepressant effect primarily through enhancement of emotional cognition and behavioral-related brain regions, and ameliorating glucose uptake competition in the left striatum and cerebellar brain regions.
- depression /
- liver-qi stagnation /
- Chaihu Shugan powder /
- microPET/CT

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图 1 与对照组相比，模型组脑葡萄糖代谢增高、减低脑区

Figure 1. Compared with the control group, brain regions glucose metabolism increased and decreased in the model group.

A: Hippocampus, corpus callosum; B: Prefrontal cortex, thalamus, inferior colliculus, M1, M2, S1, S2, cingulated cortex, corpus striatum, insular cortex, auditory cortex; C: Cerebellum, medulla oblongata, visual cortex. The red-yellow colors are the regions with increased metabolism, and the blue-green colors are the regions with decreased metabolism, and the regions with decreased metabolism and increased metabolism have overlapping colors.

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图 2 与模型组相比，低剂量组脑葡萄糖代谢增高、减低脑区

Figure 2. Compared with the model group, brain regions glucose metabolism increased and decreased in the low-dose group.

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图 3 与模型组相比，高剂量组脑葡萄糖代谢增高、减低脑区

Figure 3. Comparison with model group, brain regions glucose metabolism increased and decreased in the high- dose group.

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图 4 与低剂量组相比，高剂量组脑葡萄糖代谢增高、减低脑区

Figure 4. Comparison with the low-dose group, brain regions glucose metabolism increased and decreased in the high-dose group.

A: Hippocampus, corpus callosum; B: Prefrontal cortex, thalamu, inferior colliculus, M1, M2, S1, S2, cingulated cortex, corpus striatum, insular cortex, auditory cortex; C: Cerebellum, medulla oblongata, visual cortex. The red-yellow colors are the regions with increased metabolism, and the blue- green colors are the regions with decreased metabolism, and the regions with decreased metabolism and increased metabolism have overlapping colors.

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表 1 各组蔗糖水实验变化比较

Table 1. Comparison of sucrose water experiment in each group (%, n=10, Mean±SD

Group	Degree of sucrose water preference before intervention	Degree of sucrose water preference after 3 weeks of intervention
Control group	85.0±0.82	86.9±0.54
Model group	85.5±0.41	70.4±0.35^*
Low-dose group	86.4±0.90	82.8±0.99^▲
High-dose group	85.5±0.58	81.6±0.84^▲
^*P < 0.05 vs control group; ^▲P < 0.05 vs model group.

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表 2 各组开野实验变化比较

Table 2. Comparison of open-field experiment changes in each group (n=10, Mean±SD

Group	Times of horizontal movements	Times of vertical movements	Length of stay in the central area（s）	Number of fecal pellets
Control group	55.52±14.66	16.04±4.66	1.25±2.03	1.32±1.24
Model group	26.90±15.57^*	8.52±2.80^*	3.17±2.65	7.06±3.66^*
Low-dose group	46.04±12.33^▲	14.87±5.52^▲	2.81±2.14	1.25±1.01^▲
High-dose group	47.15±13.80^▲	11.95±3.09^▲	1.67±1.89	2.34±1.17^▲
^*P < 0.05 vs control group; ^▲P < 0.05 vs model group.

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表 3 模型组与对照组不同脑区相对葡萄糖代谢率变化比较

Table 3. Comparison of relative glucose metabolic rate in different brain regions between model group and control group (n=10, Mean±SD)

Brain region	Control group	Model group
Left corpus striatum	1.07486±0.02460	1.02725±0.03359^*
Left medulla oblongata	0.93674±0.08531	1.01784±0.08111^*
Left cerebellum	1.04118±0.09803	1.11027±0.03221^*
Left corpus callosum	1.03780±0.05123	0.99216±0.02931^*
Left M1	0.99808±0.07689	0.93636±0.04580^*
Left M2	1.06499±0.10819	0.97459±0.04030^*
Right thalamus	1.14833±0.04277	1.11027±0.03693^*
Right medulla oblongata	1.00976±0.07858	1.09288±0.09819^*
Right hippocampus	1.04963±0.03839	1.01059±0.02546^*
Right corpus callosum	1.04392±0.04199	1.00301±0.02586^*
Right prefrontal cortex	1.14400±0.04386	1.08218±0.02593^*
Right cingulated cortex	1.09671±0.10480	1.01469±0.03777^*
Right M1	1.02810±0.09376	0.94466±0.03318^*
Right M2	1.07593±0.11416	0.98556±0.03734^*
Right S1	1.00563±0.04336	0.95574±0.02484^*
Right S2	1.01604±0.03697	0.96487±0.02686^*
Right insular cortex	0.98743±0.07179	0.92576±0.03311^*
^*P < 0.05 vs control group. This experiment obtained a total of 44 sets of data. Listing all the data would take up a huge amount of space, so only the data with statistical significance is listed.

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表 4 低剂量组、高剂量组与模型组不同脑区相对葡萄糖代谢率变化比较

Table 4. Comparison of relative glucose metabolic rate in different brain regions between low-dose group, high-dose group and model group (n=10, Mean±SD)

Brain region	Model group	Low-dose group	High-dose group
Left corpus striatum	1.02725±0.03359	1.06729±0.02972^▲	1.05616±0.06592
Left medulla oblongata	1.01784±0.08111	0.95690±0.02402^▲	1.00923±0.07525
Left inferior colliculus	1.16477±0.04259	1.22799±0.06413^▲	1.21003±0.06411
Left visual cortex	0.85974±0.05589	0.79350±0.06542^▲	0.89999±0.09641^*
Left cerebellum	1.11027±0.03221	1.04803±0.03947^▲	1.06086±0.09602
Left hippocampus	1.02593±0.03364	1.06242±0.02335^▲	1.03241±0.04048
Left corpus callosum	0.99216±0.02931	1.01954±0.02372^▲	0.99209±0.07030
Left prefrontal cortex	1.10101±0.05407	1.17155±0.06835^▲	1.15035±0.07756
Left M2	0.97459±0.04030	1.01667±0.03803^▲	1.01479±0.10404
Right corpus striatum	1.04484±0.02560	1.07362±0.02495^▲	1.05920±0.05883
Right thalamus	1.11027±0.03693	1.14687±0.01397^▲	1.11287±0.06319
Right auditory cortex	0.96606±0.03982	1.01910±0.03736^▲	0.99829±0.04764
Right hippocampus	1.01059±0.02546	1.06271±0.02824^▲	1.03129±0.03607^*
Right corpus callosum	1.00301±0.02586	1.03226±0.02503^▲	1.01300±0.07025
Right prefrontal cortex	1.08218±0.02593	1.15355±0.05609^▲	1.14995±0.08731^▲
Right M1	0.94466±0.03318	0.98005±0.03661^▲	0.97561±0.09001
Right S1	0.95574±0.02484	0.98478±0.02877^▲	0.96434±0.05408
Right S2	0.96487±0.02686	0.99711±0.02877^▲	0.97511±0.05418
Right insular cortex	0.92576±0.03311	0.98170±0.04974^▲	0.96472±0.05944
^▲P < 0.05 vs model group; ^*P < 0.05 vs low-dose group

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