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Catalpol Alleviates Ischemic Stroke Through Promoting Angiogenesis and Facilitating Proliferation and Differentiation of Neural Stem Cells via the VEGF-A/KDR Pathway

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Abstract

Stroke is one of the leading causes of disability and death globally with a lack of effective therapeutic strategies. Catalpol is a bioactive compound derived from the traditional Chinese medicine Rehmannia glutinosa and it has been shown to be protective against various neurological diseases. The potential roles of catalpol against ischemic stroke are still not completely clear. In this study, we examined the effect and mechanism of catalpol against ischemic stroke using in vivo rat distal middle cerebral artery occlusion (dMCAO) and in vitro oxygen–glucose deprivation (OGD) models. We demonstrated that catalpol indeed attenuated the neurological deficits caused by dMCAO and improved neurological function. Catalpol remarkably promoted angiogenesis, promoted proliferation and differentiation of neural stem cells (NSCs) in the subventricular zone (SVZ), and prevented neuronal loss and astrocyte activation in the ischemic cortex or hippocampal dentate gyrus (DG) in vivo. The vascular endothelial growth factor receptor 2 (KDR, VEGFR-2) inhibitor SU5416 and VEGF-A shRNA were used to investigate the underlying mechanisms. The results showed that SU5416 administration or VEGF-A-shRNA transfection both attenuated the effects of catalpol. We also found that catalpol promoted the proliferation of cultured brain microvascular endothelial cells (BMECs) and the proliferation and differentiation of NSCs subjected to OGD insult in vitro. Interestingly, the impact of catalpol on cultured cells was also inhibited by SU5416. Moreover, catalpol was shown to protect NSCs against OGD indirectly by promoting BMEC proliferation in the co-cultured system. Taken together, catalpol showed therapeutic potential in cerebral ischemia by promoting angiogenesis and NSC proliferation and differentiation. The protective effects of catalpol were mediated through VEGF-A/KDR pathway activation.

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Funding

This study is supported by the National Natural Science Foundation of China (No.81873034, 81801329), a grant from Rehabilitation Medicine of Southwest University, Key Disciplines of Traditional Chinese Medicine of Chongqing City (2021–4322190044), Chongqing Natural Science Foundation (No.cstc2021jcyj-msxmX0610), Fundamental Research Funds for the Central Universities (No. SWU-KQ22018), Science and technology research project of Chongqing Education Commission (No. KJQN202100213).

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Authors and Affiliations

  1. College of Pharmaceutical Sciences, Southwest University, Chongqing, 400715, China

    Si Sun, Yitong Xu, Ningxi Yu, Meifeng Zhang, Jinghui Wang, Zhen Tian & Huifeng Zhu

  2. Department of Emergency and Critical Care Medicine, First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China

    Dong Wan

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  1. Si Sun
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Contributions

HFZ designed the study; SX, YTX, NXY, and MFZ conducted the experiments; ZT and HFZ provided guidance for the experiments; SX, ZT, and HFZ wrote the original draft; JHW and DW made the figures and searched the literature. All authors have read, edited, and approved the submitted version.

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Correspondence to Zhen Tian or Huifeng Zhu.

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Sun, S., Xu, Y., Yu, N. et al. Catalpol Alleviates Ischemic Stroke Through Promoting Angiogenesis and Facilitating Proliferation and Differentiation of Neural Stem Cells via the VEGF-A/KDR Pathway. Mol Neurobiol 60, 6227–6247 (2023). https://doi.org/10.1007/s12035-023-03459-9

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