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Targeted Energy Metabolomics Combined with Spatial Metabolomics Study on the Efficacy of Guhong Injection Against Cerebral Ischemia Reperfusion

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Abstract

Optimizing the metabolic phenotype to improve cerebral function is critical for treatment of cerebral ischemia-reperfusion (I/R) injury. Guhong injection (GHI), which comprised safflower extract and aceglutamide, is widely prescribed in Chinese medicine for the treatment of cerebrovascular diseases. In this study, a combination of LC-QQQ-MS and MALDI–MSI were utilized to explore tissue-specific metabolic alterations in the brain of I/R, as well as to evaluate the therapeutic effect of GHI. Pharmacological evaluation demonstrated that GHI can significantly improve infarction rate, neurological deficit, cerebral blood flow, and neuronal damage in I/R rats. Based on LC-QQQ-MS, 23 energy metabolites were found to be significantly altered in the I/R group compared to the sham group (P < 0.05). After GHI treatment, 12 metabolites, including G6P, TPP, NAD, citrate, succinate, malate, ATP, GTP, GDP, ADP, NADP, and FMN showed a significant tendency of returning to baseline values (P < 0.05). Based on MALDI-MSI, 4 metabolites in glycolysis and TCA, 4 metabolites in nucleic acid metabolism, 4 amino acid metabolites, and 6 metabolites were discovered and compared between the different groups in the four special regions of cortex, hippocampus, hypothalamus, and striatum. Parts of these were found to have significant changes after I/R in the special brain region, and were regulated by GHI. The study provides comprehensive and detailed information for specific metabolic reprogramming of brain tissue in rats with I/R, and the therapeutic effect of GHI.

Graphical Abstract

Schema describing the discovery strategies of integrated LC-MS and MALDI-MSI to identify cerebral ischemia reperfusion metabolic reprogramming and GHI therapeutic effects

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Data Availability

The datasets used and/or analyzed in the current study are available from the corresponding authors on reasonable request.

Abbreviations

ADP:

Adenosine diphosphate

ATP:

Denosine triphosphate

BBB:

Blood brain barrier;

CI:

Cerebral ischemia

GHI:

Guhong injection

GC–MS:

Chromatography-mass spectrometry

GDP:

Guanosine diphosphate

LC-MS/MS:

Liquid chromatography/tandem mass spectrometry

LysoPC:

Lysophosphatidylcholine

MALDI–MSI:

Matrix-assisted laser desorption ionization mass spectrometry imaging

NMR:

Nuclear magnetic resonance

PC:

Phosphatidylcholine

PI:

Phosphatidylinositol

PA:

Phosphatidic acid

tPA:

Tissue plasminogen activator

TPP:

Thiamine pyrophosphate succinate

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Acknowledgements

We want to thank the participants for taking part in the study.

Funding

The research was supported by the National Key R&D Program of China (2019YFC1708900), National Natural Science Foundation of China (Nos. 81974550, 81973711), Scientific and Technological Innovation project of China Academy of Chinese Medical Science (CI2021A04612, CI2021A05208, CI2021B017), and The Fundamental Research Funds for the Central Public Welfare Research Institutes (JBGS2021003, ZZ13-YQ-080).

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  1. Huanhuan Wang, Zhenkun Li, and Guangzhao Cao contributed equally to this work.

Authors and Affiliations

  1. Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Dong Nei Nan Xiao Jie 16, Beijing, 100700, China

    Huanhuan Wang, Zhenkun Li, Guangzhao Cao, Liying Tang, Rui Zhou, Jingjing Zhang & Hongwei Wu

  2. Experimental Research Centre, China Academy of Chinese Medical Sciences, Beijing, 100700, China

    Caifeng Li, Xianyu Li & Hongjun Yang

  3. Chinese Institute for Brain Research, Beijing, 102206, China

    Jingjing Zhang

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  1. Huanhuan Wang
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Contributions

Jingjing Zhang, Hongwei Wu, and Hongjun Yang conceived and designed the experiments; Huanhuan Wang, Guangzhao Cao, Rui Zhou, and Zhenkun Li performed the experiments; Caifeng Li, Liying Tang, and Xianyu Li analyzed the data; Huanhuan Wang and Hongwei Wu wrote the paper. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Liying Tang, Jingjing Zhang or Hongwei Wu.

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All experimental animal procedures were approved by the China Academy of Chinese Medical Sciences’ Administrative Panel on Laboratory Animal Care and performed in accordance with institutional guidelines and ethics of the committee as part of the China Academy of Chinese Medical Sciences (code, ERCCACMS21-2106-17).

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Wang, H., Li, Z., Cao, G. et al. Targeted Energy Metabolomics Combined with Spatial Metabolomics Study on the Efficacy of Guhong Injection Against Cerebral Ischemia Reperfusion. Mol Neurobiol 60, 5533–5547 (2023). https://doi.org/10.1007/s12035-023-03403-x

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