百合地黄汤加味用于卒中后抑郁症的潜在作用靶点及机制

黄思行; 吴书祎; 张平; 罗金萍; 王敏; 郭延垒; 李浩; 张莉; 强喆

doi:10.6039/j.issn.1001-0408.2023.20.07

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百合地黄汤加味用于卒中后抑郁症的潜在作用靶点及机制

药学研究 | 更新时间：2023-10-25

- 百合地黄汤加味用于卒中后抑郁症的潜在作用靶点及机制
- The potential targets and mechanisms of modified Baihe dihuang decoction applied in post-stroke depression
- 中国药房 2023年34卷第20期页码：2483-2489
- 作者机构：
  
  1.重庆市中药研究院，重庆　400065
  2.重庆中医药学院中药系，重庆　402760
  3.重庆医科大学中医药学院，重庆　400016
- 作者简介：
  
  副研究员，硕士。研究方向：中药药理学。E-mail：25967952@qq.com
  副研究员，博士。研究方向：分子药理学。E-mail：qiangzhe@cqtcm.edu.cn
- 基金信息：
  
  重庆市基本科研业务费项目(cstc2020jxjl-jbky10004)
- DOI：10.6039/j.issn.1001-0408.2023.20.07
  中图分类号： R964;R966
- 纸质出版日期：2023-10-30，
  
  收稿日期：2023-04-05，
  
  修回日期：2023-08-29，
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黄思行,吴书祎,张平等.百合地黄汤加味用于卒中后抑郁症的潜在作用靶点及机制 ^Δ[J].中国药房,2023,34(20):2483-2489.

HUANG Sixing,WU Shuyi,ZHANG Ping,et al.The potential targets and mechanisms of modified Baihe dihuang decoction applied in post-stroke depression[J].ZHONGGUO YAOFANG,2023,34(20):2483-2489.
黄思行,吴书祎,张平等.百合地黄汤加味用于卒中后抑郁症的潜在作用靶点及机制 ^Δ[J].中国药房,2023,34(20):2483-2489. DOI： 10.6039/j.issn.1001-0408.2023.20.07.

HUANG Sixing,WU Shuyi,ZHANG Ping,et al.The potential targets and mechanisms of modified Baihe dihuang decoction applied in post-stroke depression[J].ZHONGGUO YAOFANG,2023,34(20):2483-2489. DOI： 10.6039/j.issn.1001-0408.2023.20.07.

摘要

目的

探讨百合地黄汤加味（MBD/BDD）用于卒中后抑郁症（PSD）的潜在作用靶点及机制。

方法

通过网络药理学方法挖掘MBD/BDD治疗PSD的潜在靶点和关键途径。以局灶性脑缺血手术结合慢性不可预见的温和应激建立PSD模型大鼠，并随机分为PSD模型组、MBD/BDD组（12.6 g/kg，以生药总量计）、盐酸氟西汀（FLX）组（阳性对照，2.3 mg/kg），另设空白对照组，每组8只。各药物组大鼠灌胃相应药液，每天1次，连续21 d。通过旷场实验、强迫游泳实验评价MBD/BDD对模型大鼠抑郁样症状的干预效果；剖取各组大鼠脑组织并提取总RNA，进行转录组测序和生物信息学分析，并基于上述结果对变化显著的基因和常见神经营养因子进行mRNA和蛋白水平表达验证。

结果

共获得MBD/BDD抗抑郁相关靶基因131个（如

IL1B

、

AKT1

等），涉及神经活性配体-受体相互作用、环磷酸腺苷等信号通路。MBD/BDD可显著延长或增加PSD模型大鼠在中心方格花费的总时间及行进的总距离，显著缩短累计不动时间（

＜0.05）。经MBD/BDD干预后，大鼠脑组织中发生变化的基因远多于FLX组，且PSD模型组、MBD/BDD组、FLX组的基因谱存在明显差异；MBD/BDD组与PSD模型组之间的差异表达基因（DEGs）共1 351个，其中178个显著下调、1 173个显著上调（

＜0.05）；这1 351个DEGs涉及神经元分化、化学突触传递调节等，并在轴突引导、胆碱能突触和神经活性配体-受体相互作用方面显著富集；MBD/BDD组大鼠脑组织中上调幅度排名前30位的基因均与神经元增殖、发育、分化和迁移有关。经MBD/BDD干预后，大鼠脑组织中

Fezf2

、

Arx

、

Ostn

、

Nrgn

基因和脑源性神经营养因子、酪氨酸激酶受体B蛋白的相对表达量均显著升高（

＜0.05）。

结论

MBD/BDD的抗PSD作用可能与上调神经元增殖、发育、分化和迁移相关基因的表达，促进神经结构和功能的修复有关。

Abstract

OBJECTIVE

To explore the potential targets and mechanisms of the modified Baihe dihuang decoction （MBD/BDD） applied in post-stroke depression （PSD）.

METHODS

Network pharmacology was used to mine the potential targets and key pathways of MBD/BDD in the treatment of PSD. PSD model rats were induced by focal cerebral ischemia surgery combined with chronic unforeseen mild stress， and then were randomly divided into PSD model group， MBD/BDD group （12.6 g/kg， by raw drug）， and fluoxetine hydrochloride （FLX） group （positive control， 2.3 mg/kg）； a blank control group was also set up， with 8 rats in each group. Each administration group was given a corresponding medication solution by gavage once a day for 21 consecutive days. The intervention effect of MBD/BDD on depression-like symptoms in model rats was evaluated by open field and forced swimming tests. The brain tissues of rats in each group were dissected and total RNA was extracted for transcriptome sequencing and bioinformatics analysis. The mRNA and protein expressions of genes with significant changes and common neurotrophic factors were verified based on the above results.

RESULTS

A total of 131 MBD/BDD antidepressant-related target genes were obtained （such as

IL1B

and

AKT1

， etc.）， which were closely related to neural active ligand-receptor interactions and cyclic adenosine monophosphate signaling pathway. MBD/BDD could significantly prolong or increase the total time spent and distance traveled in the central grid of PSD model rats， and significantly shorten the cumulative immobility time （

＜0.05）. After treatment with MBD/BDD， the number of genes that changed in rat brain tissue was much higher than that in the FLX group， and there were significant differences in gene profiles among the PSD model group， MBD/BDD group， and FLX group. There were 1 351 differentially expressed genes （DEGs） between the MBD/BDD group and the PSD model group， of which 178 were significantly down-regulated and 1 173 were significantly up-regulated （

＜0.05）. Above 1 351 DEGs were involved in neuronal differentiation， chemical synaptic transmission regulation. They were significantly enriched in axonal guidance， cholinergic synapses and neuroactive ligand-receptor interactions. The top 30 genes in terms of up-regulation in the brain tissue of rats of MBD/BDD group were all associated with neuronal proliferation， development， differentiation， and migration. After MBD/BDD intervention， the expressions of

Fezf2

，

Arx

，

Ostn

，

Nrgn

genes， brain-derived neurotrophic factor and tyrosine kinase receptor B protein in brain tissue of rats were significantly increased （

＜0.05）.

CONCLUSIONS

The anti-PSD effect of MBD/BDD may be related to the up-regulation of the expression of genes related to neuronal proliferation， development， differentiation and migration， as well as the promotion of neural structural and functional repair.

关键词

百合地黄汤加味卒中后抑郁网络药理学转录组学神经保护作用

Keywords

post-stroke depressionnetwork pharmacologytranscriptomicsneuroprotection

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