Intervention Effect of Dachuanxiong Fang Multi-component Preparation on Acute Migraine Rat Model by Urine Metabolomics

Shi-yu MA; Lan SHEN; Xiao LIN; Yi FENG

doi:10.13422/j.cnki.syfjx.20191705

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Intervention Effect of Dachuanxiong Fang Multi-component Preparation on Acute Migraine Rat Model by Urine Metabolomics

Drug Metabolism | 更新时间：2021-02-09

- Intervention Effect of Dachuanxiong Fang Multi-component Preparation on Acute Migraine Rat Model by Urine Metabolomics
- Chinese Journal of Experimental Traditional Medical Formulae Vol. 25, Issue 18, Pages: 101-107(2019)
- 作者机构：
  
  1.上海中医药大学　中药学院，上海　 201203；
  2.上海交通大学　医学院　附属瑞金医院，上海　 200012；
  3.上海中医药大学　中药现代制剂技术教育部工程研究中心，上海　 201203
- 作者简介：
- 基金信息：
- DOI：10.13422/j.cnki.syfjx.20191705
  CLC： R2-0; R22; R285.5; R289
- Received：02 January 2019，
  
  Published Online：17 May 2019，
  
  Published：20 September 2019
- 稿件说明：
移动端阅览
Shi-yu MA, Lan SHEN, Xiao LIN, et al. Intervention Effect of Dachuanxiong Fang Multi-component Preparation on Acute Migraine Rat Model by Urine Metabolomics[J]. Chinese journal of experimental traditional medical formulae, 2019, 25(18): 101-107.
DOI：

Shi-yu MA, Lan SHEN, Xiao LIN, et al. Intervention Effect of Dachuanxiong Fang Multi-component Preparation on Acute Migraine Rat Model by Urine Metabolomics[J]. Chinese journal of experimental traditional medical formulae, 2019, 25(18): 101-107. DOI： 10.13422/j.cnki.syfjx.20191705.

摘要

目的：

考察大川芎方多组分中药制剂对急性偏头痛大鼠尿液中内源性代谢产物的影响，通过尿液代谢组学技术探讨该药可能的作用机制。

方法：

采用40只SD雄性大鼠随机分为5组，分别为正常组、模型组和大川芎方多组分中药制剂低、中、高剂量组(0.19，0.37，0.74 g·kg

－1

)，每组8只。除正常组外，其余各组大鼠采用皮下注射10 mg·kg

－1

硝酸甘油方法制备急性偏头痛的模型。造模成功后，大川芎方多组分中药制剂组灌胃给予不同剂量的大川芎方多组分中药制剂。给药0.5 h后腹主动脉取血，采用酶联免疫吸附测定(ELISA)检测血浆中血清素5-羟色胺(5-HT)，5-羟基吲哚乙酸(5-HIAA)，一氧化氮(NO)，一氧化氮合酶(NOS)，降钙素基因相关肽(CGRP)及多巴胺(DA)含量；采用免疫组化对正常组及模型组大鼠下丘脑和脑干部位5-HT和NOS蛋白表达进行分析，并通过平均光密度值进行统计；采用UPLC-TOF/MS，结合主成分分析(PCA)对不同组别大鼠进行尿液代谢组学分析，并发现潜在的生物标记物；通过MetaboAnalyst 3.0软件对差异代谢物进行代谢通路分析。

结果：

与正常组比较，模型组大鼠体内的神经递质均有极显著性差异(

0.01)，说明急性偏头痛大鼠模型已建立；与模型组比较，各给药组体内的神经递质均有显著性差异(

0.05，

0.01)，说明给予大川芎方多组分中药制剂可调节大鼠体内的神经递质含量。根据UPLC-TOF/MS分析，共发现10种潜在的差异代谢物。大川芎方多组分中药制剂给药组可降低模型组中色氨酸、缬氨酸的含量，升高

-氨基丁酸(GABA)，乳酸，

-羟丁酸的含量。根据代谢通路预测研究，发现相关性较大的代谢通路为丙氨酸、天冬氨酸与谷氨酸代谢，丙酸代谢，氮代谢及色氨酸代谢。

结论：

大川芎方多组分中药制剂对急性偏头痛大鼠模型体内的差异代谢物有一定的回调作用，其作用机制主要与氨基酸代谢有关，特别是犬尿氨酸的代谢。

Abstract

Objective:

To investigate the intervention effect of Dachuanxiong Fang multi-component preparation on acute migraine rats

in order to explore the possible mechanism by using urine metabolomics technology.

Method:

The forty SD rats were randomly divided into 5 groups (

=8)

control group

model group

low-dose Dachuanxiong Fang multi-component preparation (DCXF) group (0.19 g·kg

-1

)

medium-dose DCXF group (0.37 g·kg

-1

)

and high-dose DCXF group (0.74 g·kg

-1

). Rats were subcutaneously injected with 10 mg·kg

-1

nitroglycerin for modeling

and Dachuanxiong Fang multi-component preparation was administered through intragastric administration. After half an hour of administration

blood was collected from the abdominal aorta

and the content of 5-hydroxytryptamine (5-HT)

5-hydroxyindole-3-acetic acid (5-HIAA)

nitric oxide (NO)

nitric oxide synthase (NOS)

calcitonlin gene related peplide (CGRP)

dopamine(DA) in plasma were determined by enzyme-linked immuno sorbent assay (ELISA) kits. The contents of 5-HT and NOS in the hypothalamus and brainstem of the control group and the model group were analyzed

and the average optical density value was used for statistical analysis. UPLC-TOF/MS combined with principal component analysis (PCA) analysis was used to analyze different groups of rats and discover differential metabolites. Differential metabolites were analyzed by MetaboAnalyst 3.0 software for possible metabolic pathways.

Result:

After modeling

compared with the control group

the content of neurotransmitters in the model group was significantly increased (

0.01). After the intervention with Dachuanxiong Fang multi-component preparation

compared with the model group

the content of neurotransmitters was significantly decreased (

0.05

0.01). Based on UPLC-TOF/MS analysis

10 potential biomarkers were found. After the intervention with Dachuanxiong multi-component preparation

the contents of tryptophan and proline were down-regulated

while the contents of gamma-aminobutyric acid(GABA)

lactic acid and

-hydroxybutyrate showed an upward trend. According to the metabolic pathway prediction study

metabolic pathways with a higher correlation were found to be alanine

aspartic acid and glutamate metabolism

propionic acid metabolism

nitrogen metabolism and tryptophan metabolism.

Conclusion:

The possible metabolism pathway of Dachuanxiong Fang multi-component preparation is mainly amino acid metabolism in urine

and kynurenine is also the product of tryptophan metabolism pathway. The kynurenine metabolic pathway is also one of the main pathways of tryptophan metabolism.

关键词

Keywords

references

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