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Neurogenesis and Proliferation of Neural Stem/Progenitor Cells Conferred by Artesunate via FOXO3a/p27Kip1 Axis in Mouse Stroke Model

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Abstract

Promoting neurogenesis and proliferation of endogenous neural stem/progenitor cells (NSPCs) is considered a promising strategy for neurorehabilitation after stroke. Our previous study revealed that a moderate dose of artesunate (ART, 150 mg/kg) could enhance functional recovery in middle cerebral artery occlusion (MCAO) mice. This study aimed to investigate the effects of ART treatment on neurogenesis and proliferation of NSPCs using a rodent MCAO model. MRI results indicated that the ischemic brain volume of MCAO mice was reduced by ART treatment. The results of diffusion tensor imaging, electron microscopic, and immunofluorescence of Tuj-1 also revealed that ischemia-induced white matter lesion was alleviated by ART treatment. After ischemia/reperfusion, the proportion of Brdu + endogenous NSPCs in the ipsilateral subventricular zone and peri-infarct cortex was increased by ART treatment. Furthermore, the neuro-restorative effects of ART were abolished by the overexpression of FOXO3a. These findings suggested that ART could rescue ischemia/reperfusion damage and alleviate white matter injury, subsequently contributing to post-stroke functional recovery by promoting neurogenesis and proliferation of endogenous NSPCs via the FOXO3a/p27Kip1 pathway.

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Data Availability

Not applicable and the datasets used in this study were available from the corresponding author upon reasonable request.

The Ethics Committee of the Third Military Medical University approved all the animal work protocols (approval no. AMUWEC20201153). The experiments were performed in concordance with Animal Research standards: Reporting of In Vivo Experiments (ARRIVE) guidelines.

Abbreviations

NSPCs:

Neural stem/progenitor cells

ART:

Artesunate

MCAO:

Middle cerebral artery occlusion

FOXO3a:

Forkhead box O3a

p27kip1 :

Cyclin-dependent kinase inhibitor 1B

CDK2:

Cyclin-dependent Kinase 2

MRI:

Magnetic resonance imaging

DTI:

Diffusion tensor imaging

FA:

Fractional anisotropy values

ADC:

Apparent diffusion coefficient value

IC:

Internal capsule

SVZ:

Subventricular zone

SGZ:

Subgranular zone of hippocampal dentate gyrus

TTC:

2, 3, 5-Triphenyltetrazolium hydrochloride

BrdU:

Bromodeoxyuridine

DCX:

Doublecortin

Tuj-1:

Neuron-specific class III beta-tubulin

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Funding

This study was supported by the Military Medicine Pre-research Project of Army Medical University(2018XYY11), National Natural Science Foundation of China (81901267), the Natural Science Foundation of Chongqing (Grant no. cstc2019jcyj-msxmX0458), and Youth Natural Science Foundation of Xinjiang (2022D01C346). The funders were not involved in study design, data collection/interpretation, and the decision to submit the publication results.

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Author notes

  1. Kaiyuan Zhang and Yang Yang contributed equally to this work.

Authors and Affiliations

  1. Department of Neurosurgery, Southwest Hospital, the Third Military Medical University (Army Military Medical University), Chongqing, China

    Kaiyuan Zhang, Yang Yang, Hongfei Ge, Ju Wang, Xuejiao Lei, Xuezhu Chen, Hua Feng & Liang Tan

  2. Department of Neurosurgery, General Hospital of Xinjiang Military Command, Urumqi, Xinjiang, China

    Kaiyuan Zhang

  3. Department of Neurosurgery, 904Th Hospital of the PLA, Medical School of Anhui Medical University, Wuxi, Jiangsu, China

    Yang Yang

  4. Department of Electrical and Computer Engineering, Faculty of Science and Technology, University of Macau, Macau, China

    Feng Wan & Liang Tan

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  1. Kaiyuan Zhang
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Contributions

KYZ performed most of the experiments, with assistance from YY and XZC XJL, and YY analyzed the results and produced the figures. KYZ conducted statistical analysis. FW and HFG performed animal experiments. XZC, XJC, and HFG conducted immunoblotting and immunostaining. KYZ drafted the manuscript. YY and LT reviewed the manuscript. LT and HF designed experiments. All authors approved the final version of the document.

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Correspondence to Liang Tan.

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Zhang, K., Yang, Y., Ge, H. et al. Neurogenesis and Proliferation of Neural Stem/Progenitor Cells Conferred by Artesunate via FOXO3a/p27Kip1 Axis in Mouse Stroke Model. Mol Neurobiol 59, 4718–4729 (2022). https://doi.org/10.1007/s12035-021-02710-5

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