<sup>1</sup>H-NMR Metabolomic Analysis of Brain Tissue of CUMS-Induced Depressed Mice Intervened by Iridoid Part of Valerianae Jatamansi Rhizoma et Radix

Yong-biao LI; Lan-lan WU; Yu-qing FAN; Chang CHEN; Jian GAO; Zhong-feng LI; Ru-yi CUI; Xin-yi WANG; Zhi-yong YAN; An LIU

doi:10.13422/j.cnki.syfjx.20201249

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¹H-NMR Metabolomic Analysis of Brain Tissue of CUMS-Induced Depressed Mice Intervened by Iridoid Part of Valerianae Jatamansi Rhizoma et Radix

Drug Metabolism | 更新时间：2020-09-16

- ¹H-NMR Metabolomic Analysis of Brain Tissue of CUMS-Induced Depressed Mice Intervened by Iridoid Part of Valerianae Jatamansi Rhizoma et Radix
- Chinese Journal of Experimental Traditional Medical Formulae Vol. 26, Issue 19, Pages: 195-203(2020)
- 作者机构：
  
  1.西南交通大学生命科学与工程学院，成都 610031
  2.中国中医科学院中药研究所，北京 100700
  3.北京中医药大学第三附属医院，北京 100029
  4.首都师范大学，北京 100048
- 作者简介：
- 基金信息：
- DOI：10.13422/j.cnki.syfjx.20201249
  CLC： R22;R969.1;R971;R445.2
- Received：19 December 2019，
  
  Published Online：14 April 2020，
  
  Published：05 October 2020
- 稿件说明：
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李永彪,吴兰兰,樊玉青等.蜘蛛香环烯醚萜部位干预CUMS致抑郁小鼠脑组织的¹H-NMR代谢组学分析[J].中国实验方剂学杂志,2020,26(19):195-203.

LI Yong-biao,WU Lan-lan,FAN Yu-qing,et al.¹H-NMR Metabolomic Analysis of Brain Tissue of CUMS-Induced Depressed Mice Intervened by Iridoid Part of Valerianae Jatamansi Rhizoma et Radix[J].Chinese Journal of Experimental Traditional Medical Formulae,2020,26(19):195-203.
李永彪,吴兰兰,樊玉青等.蜘蛛香环烯醚萜部位干预CUMS致抑郁小鼠脑组织的¹H-NMR代谢组学分析[J].中国实验方剂学杂志,2020,26(19):195-203. DOI： 10.13422/j.cnki.syfjx.20201249.

LI Yong-biao,WU Lan-lan,FAN Yu-qing,et al.¹H-NMR Metabolomic Analysis of Brain Tissue of CUMS-Induced Depressed Mice Intervened by Iridoid Part of Valerianae Jatamansi Rhizoma et Radix[J].Chinese Journal of Experimental Traditional Medical Formulae,2020,26(19):195-203. DOI： 10.13422/j.cnki.syfjx.20201249.

摘要

目的

利用代谢组学技术分析慢性温和不可预知应激（CUMS）抑郁模型小鼠脑组织样本，寻找与抑郁相关的差异代谢物，探讨蜘蛛香环烯醚萜部位（IEFV）可能的抗抑郁作用机制。

方法

42只昆明小鼠随机分为6组，包括正常组，模型组，氟西汀组（2.5 mg·kg

-1

），IEFV低、中、高剂量组（给药剂量分别为5.73，11.47，22.94 mg·kg

-1

）。采用CUMS对小鼠造模，以IEFV及阳性药（氟西汀）为干预药物，用行为指标和生化指标进行药效学评价。采用核磁共振氢谱（

H-NMR）代谢组学技术分析IEFV对CUMS抑郁模型小鼠脑组织中内源性物质的影响，结合多变量统计分析方法来确认差异代谢物，并对差异代谢物参与的代谢通路进行富集。

结果

造模后，小鼠的不动时间大幅度提高、蔗糖偏好率明显下降，兴奋性神经递质5-羟色胺和去甲肾上腺素显著下降，表明造模成功。给予IEFV和氟西汀后，小鼠不动时间、蔗糖偏好率和兴奋性神经递质向正常水平回调，提示给药后抑郁状态得到了一定程度的缓解。脑组织中内源性代谢物主成分分析（PCA）结果显示，模型组可与正常组明显分开，同时IEFV低、中、高剂量组和氟西汀组均显示有偏离模型组向正常组靠拢的趋势，与行为学结果一致。模型组与正常组进行正交偏最小二乘法-判别分析（OPLS-DA）得到了16个变化显著的差异代谢物，包括12个水溶性差异代谢物和4个脂溶性差异代谢物。通过MetPA数据库分析得到7条潜在靶标代谢通路，包括三羧酸循环（TCA），牛磺酸和亚牛磺酸的代谢，丙氨酸、天冬氨酸和谷氨酸代谢等。IEFV高剂量组可显著回调11种差异代谢物。

结论

IEFV可能主要通过影响能量代谢，氨基酸代谢和神经递质水平发挥抗抑郁作用，可为IEFV抗抑郁作用机制的深入研究提供参考依据。

Abstract

Objective

Metabolomics was used to analyze the brain tissue samples of model mice with chronic unpredictable mild stress (CUMS) depression

in order to find out the differential metabolites related to depression and to explore the possible antidepressant mechanism of iridoid part of Valerianae Jatamansi Rhizoma et Radix (IEFV).

Method

Forty-two Kunming mice were randomly divided into 6 groups

including the normal group

the model group

the fluoxetine group (2.5 mg·kg

-1

) and the IEFV low

medium

and high dose groups (doses were 5.73

11.47

22.94 mg·kg

-1

respectively). The behavioral and biochemical indicators of CUMS model mice were used for pharmacodynamic evaluation with IEFV and a positive drug (fluoxetine) as the intervention drugs. Then

the effect of IEFV on endogenous substances of the brain tissue in CUMS model mice were analyzed by nuclear magnetic resonance hydrogen spectrum (

H-NMR) metabolomics

and multivariate statistical analysis was used to identify the differential metabolites and to enrich the metabolic pathways involved in the differential metabolites.

Result

After modeling

the immobility time of the model mice increased significantly

their sucrose preference rate and the excitatory neurotransmitters [5-hydroxytryptamine (5-HT) and norepinephrine (NE)] decreased significantly

indicating the success of modeling. The depression was relieved after IEFV administration

mainly manifested by the recovery of the immobility time

sucrose preference rate and the excitatory neurotransmitters (5-HT and NE). Principal component analysis (PCA) of endogenous metabolites in brain tissue showed that the model group could be significantly separated from the normal group

while the IEFV groups and fluoxetine group all showed a trend of deviating from the model group to the normal group

which was consistent with the behavioral results. The results of orthogonal partial least squares discriminant analysis (OPLS-DA) showed that there were 16 different metabolites between the model group and the normal group

including 12 water-soluble metabolites and 4 liposoluble metabolites. Seven potential metabolism pathways were obtained through MetPA analysis

including metabolism of phenylalanine

metabolism of phenylalanine

tyrosine and tryptophan

metabolism of taurine and hypotaurine acid

metabolism of alanine

aspartic acid and glutamic acid

biosynthesis of valine

leucine and isoleucine

metabolism of

-glutamine and

-glutamate and tricarboxylic acid cycle (TCA). IEFV-high dose group could significantly recall 11 differential metabolites.

Conclusion

IEFV may play an antidepressant role mainly by affecting energy metabolism

amino acid metabolism and neurotransmitter levels

which provides a reference for further study on the antidepressant mechanism of IEFV.

关键词

Keywords

references

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⁰

1H-NMR Metabolomic Analysis of Brain Tissue of CUMS-Induced Depressed Mice Intervened by Iridoid Part of Valerianae Jatamansi Rhizoma et Radix

DOI：10.13422/j.cnki.syfjx.20201249

摘要

Abstract

关键词

Keywords

references

¹H-NMR Metabolomic Analysis of Brain Tissue of CUMS-Induced Depressed Mice Intervened by Iridoid Part of Valerianae Jatamansi Rhizoma et Radix