Journal of Ginseng Research

The Korean Society of Ginseng (고려인삼학회)
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Ginsenoside compound K protects against cerebral ischemia/ reperfusion injury via Mul1/Mfn2-mediated mitochondrial dynamics and bioenergy

  • Qingxia Huang (Research Center of Traditional Chinese Medicine, College of Traditional Chinese Medicine, Changchun University of Chinese Medicine) ;
  • Jing Li (Northeast Asia Research Institute of Traditional Chinese Medicine, Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Changchun University of Chinese Medicine) ;
  • Jinjin Chen (Northeast Asia Research Institute of Traditional Chinese Medicine, Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Changchun University of Chinese Medicine) ;
  • Zepeng Zhang (Research Center of Traditional Chinese Medicine, College of Traditional Chinese Medicine, Changchun University of Chinese Medicine) ;
  • Peng Xu (Department of Encephalopathy, College of Traditional Chinese Medicine, Changchun University of Chinese Medicine) ;
  • Hongyu Qi (Northeast Asia Research Institute of Traditional Chinese Medicine, Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Changchun University of Chinese Medicine) ;
  • Zhaoqiang Chen (Northeast Asia Research Institute of Traditional Chinese Medicine, Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Changchun University of Chinese Medicine) ;
  • Jiaqi Liu (Northeast Asia Research Institute of Traditional Chinese Medicine, Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Changchun University of Chinese Medicine) ;
  • Jing Lu (Research Center of Traditional Chinese Medicine, College of Traditional Chinese Medicine, Changchun University of Chinese Medicine) ;
  • Mengqi Shi (Department of Graduate Administration, College of Traditional Chinese Medicine, Changchun University of Chinese Medicine) ;
  • Yibin Zhang (Department of Encephalopathy, College of Traditional Chinese Medicine, Changchun University of Chinese Medicine) ;
  • Ying Ma (Department of Encephalopathy, College of Traditional Chinese Medicine, Changchun University of Chinese Medicine) ;
  • Daqing Zhao (Northeast Asia Research Institute of Traditional Chinese Medicine, Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Changchun University of Chinese Medicine) ;
  • Xiangyan Li (Northeast Asia Research Institute of Traditional Chinese Medicine, Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Changchun University of Chinese Medicine)
  • Received : 2022.06.06
  • Accepted : 2022.10.11
  • Published : 2023.05.01
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Abstract

Background: Ginsenoside compound K (CK), the main active metabolite in Panax ginseng, has shown good safety and bioavailability in clinical trials and exerts neuroprotective effects in cerebral ischemic stroke. However, its potential role in the prevention of cerebral ischemia/reperfusion (I/R) injury remains unclear. Our study aimed to investigate the molecular mechanism of ginsenoside CK against cerebral I/R injury. Methods: We used a combination of in vitro and in vivo models, including oxygen and glucose deprivation/reperfusion induced PC12 cell model and middle cerebral artery occlusion/reperfusion induced rat model, to mimic I/R injury. Intracellular oxygen consumption and extracellular acidification rate were analyzed by Seahorse multifunctional energy metabolism system; ATP production was detected by luciferase method. The number and size of mitochondria were analyzed by transmission electron microscopy and MitoTracker probe combined with confocal laser microscopy. The potential mechanisms of ginsenoside CK on mitochondrial dynamics and bioenergy were evaluated by RNA interference, pharmacological antagonism combined with co-immunoprecipitation analysis and phenotypic analysis. Results: Ginsenoside CK pretreatment could attenuate mitochondrial translocation of DRP1, mitophagy, mitochondrial apoptosis, and neuronal bioenergy imbalance against cerebral I/R injury in both in vitro and in vivo models. Our data also confirmed that ginsenoside CK administration could reduce the binding affinity of Mul1 and Mfn2 to inhibit the ubiquitination and degradation of Mfn2, thereby elevating the protein level of Mfn2 in cerebral I/R injury. Conclusion: These data provide evidence that ginsenoside CK may be a promising therapeutic agent against cerebral I/R injury via Mul1/Mfn2 mediated mitochondrial dynamics and bioenergy.

Keywords

Acknowledgement

This work was supported by the National Natural Science Foundation of China, China (Grant No. 82104432 and U19A2013), the National Key Research and Development Program of China, China (Grant No. 2019YFC1709902), the Science and Technology Development Plan Project of Jilin Province, China (Grant No. YDZJ202201ZYTS270, 202002053JC and 20200201419JC), and the Jilin Provincial Administration of Traditional Chinese Medicine, China (Grant No. 20222222). We thank LetPub (www.letpub.com) for its linguistic assistance during the preparation of this manuscript.

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