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Astragaloside VI Promotes Neural Stem Cell Proliferation and Enhances Neurological Function Recovery in Transient Cerebral Ischemic Injury via Activating EGFR/MAPK Signaling Cascades

  • Xi Chen
  • Hao Wu
  • Hansen Chen
  • Qi Wang
  • Xue-jiao Xie
  • Jiangang Shen
Article
  • 143 Downloads

Abstract

Radix Astragali (AR) is a commonly used medicinal herb for post-stroke disability in Traditional Chinese Medicine but its active compounds for promoting neurogenic effects are largely unknown. In the present study, we tested the hypothesis that Astragaloside VI could be a promising active compound from AR for adult neurogenesis and brain repair via targeting epidermal growth factor (EGF)-mediated MAPK signaling pathway in post-stroke treatment. By using cultured neural stem cells (NSCs) and experimental stroke rat model, we investigated the effects of Astragaloside VI on inducing NSCs proliferation and self-renewal in vitro, and enhancing neurogenesis for the recovery of the neurological functions in post-ischemic brains in vivo. For animal experiments, rats were undergone 1.5 h middle cerebral artery occlusion (MCAO) plus 7 days reperfusion. Astragaloside VI (2 μg/kg) was daily administrated by intravenous injection (i.v.) for 7 days. Astragaloside VI treatment promoted neurogenesis and astrogenic formation in dentate gyrus zone, subventricular zone, and cortex of the transient ischemic rat brains in vivo. Astragaloside VI treatment enhanced NSCs self-renewal and proliferation in the cultured NSCs in vitro without affecting NSCs differentiation. Western blot analysis showed that Astragaloside VI up-regulated the expression of nestin, p-EGFR and p-MAPK, and increased neurosphere sizes, whose effects were abolished by the co-treatment of EGF receptor inhibitor gefitinib and ERK inhibitor PD98059. Behavior tests revealed that Astragaloside VI promoted the spatial learning and memory and improved the impaired motor function in transient cerebral ischemic rats. Taken together, Astragaloside VI could effectively activate EGFR/MAPK signaling cascades, promote NSCs proliferation and neurogenesis in transient cerebral ischemic brains, and improve the repair of neurological functions in post-ischemic stroke rats. Astragaloside VI could be a new therapeutic drug candidate for post-stroke treatment.

Keywords

Astragaloside VI Transient cerebral ischemia Neural stem cell Proliferation Epidermal growth factor 

Abbreviations

EGF

Epidermal growth factor

NSCs

Neural stem cells

MCAO

Middle cerebral artery occlusion

SVZ

Subventricular zone

LV

Lateral ventricles

DG

Dentate gyrus

AsVI

Astragaloside VI

TCM

Traditional Chinese medicine

Notes

Acknowledgments

We appreciate Professor Guowei Qin from Shanghai Institute of Meteria Medica for providing the sample of Astrogaloside VI for our study.

Authors’ Contribution

The work was performed and accomplished by all authors. S-JG and XC received fund and designed the experiments. XC, HW, and C-HS conducted the experiments and statistical analyses. X-XJ and QW provided technical support for animal experiments, experimental design, data interpretation, and gave comments on the manuscript. XC and S-JG wrote the manuscript. All authors have read and approved the final manuscript.

Funding

This study was supported by the grants from Shenzhen Science and Technology Innovation Commission (JCYJ20150402152005623), 2011 State Key Project of National Natural Foundation of China (No. 81630101,SIRI/04/09/2014/2), and National Natural Foundation of China (No. 81703741).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

Animal experimental protocols were conducted in accordance with the national and institutional guidelines on ethics and biosafety, which were approved and regulated by the Committee on the Use of Live Animals in Teaching and Research (CULATR), HKU. This article does not contain any studies with human participants performed by any of the authors.

Supplementary material

12035_2018_1294_Fig10_ESM.png (82 kb)
ESM 1

Effects of As I, AS II, AS III, AS V (from 50 nM to 50 uM) on the C17.2 NPCs cell viability detected by MTT assay. (PNG 82 kb)

12035_2018_1294_MOESM1_ESM.tif (481 kb)
High resolution image (TIF 481 kb)
12035_2018_1294_Fig11_ESM.png (5.7 mb)
ESM 2

As VI dose-dependently induces proliferation of primary cultured NSCs. NSCs were dual-immunostained with Nestin (red) and BrdU(green). (PNG 5873 kb)

12035_2018_1294_MOESM2_ESM.tif (11.1 mb)
High resolution image (TIF 11342 kb)
12035_2018_1294_Fig12_ESM.png (72 kb)
ESM 3

Laser Doppler detections for perfusion reduction rates (%) in different groups of rats after MCAO ischemic surgery. (PNG 72 kb)

12035_2018_1294_MOESM3_ESM.tif (721 kb)
High resolution image (TIF 720 kb)
12035_2018_1294_Fig13_ESM.png (667 kb)
ESM 4

A, Chemical structure of Astragaloside VI. B, LC-MS-HPLC analysis of the purity of Astragaloside VI (AS-VI) and the purity identified was over 99.9%. (PNG 666 kb)

12035_2018_1294_MOESM4_ESM.tif (1.6 mb)
High resolution image (TIF 1681 kb)

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Authors and Affiliations

  1. 1.Department of Core FacilityThe People’s Hospital of Bao-anShenzhenChina
  2. 2.The 8th people’s Hospital of ShenzhenThe Affiliated Bao-an Hospital of Southern Medical UniversityShenzhenChina
  3. 3.School of Chinese Medicine, Li Ka Shing Faculty of MedicineThe University of Hong KongHong KongChina
  4. 4.Institute of Clinical PharmacologyGuangzhou University of Chinese MedicineGuangzhouChina
  5. 5.School of Traditional Chinese MedicineHunan University of Chinese MedicineChangshaChina

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