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The Impact of Dipyridamole on Disease-Associated Microglia Phenotypic Transformation in White Matter Lesions Induced by Chronic Cerebral Hypoperfusion

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Abstract

White matter lesions (WMLs) resulting from chronic cerebral hypoperfusion (CCH) are the leading cause of vascular dementia (VaD). This study aimed to investigate whether dipyridamole could alleviate WMLs by regulating the phenotype of disease-associated microglia (DAM) through equilibrative nucleoside transporter 2 (ENT2) and adenosine A2A receptor (Adora2a) and to clarify the underlying molecular mechanisms. CCH rat models were constructed to mimic VaD. Morris water maze and Luxol Fast Blue staining were employed to assess cognitive function and quantify the severity of WMLs, respectively. Immunofluorescent staining was performed to analyze the activation of glial cells and the phenotypic transformation of DAM. Additionally, levels of ENT2, proteins in the NF-κB and ERK1/2 pathways and inflammatory cytokines were detected. The results indicated that dipyridamole diminished the activation and proliferation of microglia and astrocytes, increased the expression of myelin basic protein and ameliorated WMLs and cognitive decline in CCH rats. Further study revealed that dipyridamole decreased the expression of ENT2 and inhibited the activation of ERK1/2 and NF-κB signaling pathways, which ultimately converted DAM to anti-inflammatory phenotype and suppressed the levels of TNF-α, IL-1β, IL-6 in WMLs. However, Adora2a inhibitor (SCH58261) attenuated above effects. Our study demonstrates that dipyridamole facilitates the conversion of DAM to the anti-inflammatory phenotype through ENT2/Adora2a pathway and inhibits the activation of ERK1/2 and NF-κB signaling pathways, thereby alleviating neuroinflammation in WMLs. The current findings establish the basis for using dipyridamole to treat VaD.

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Data Availability

The data used in our study are available from the corresponding author upon reasonable request.

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Acknowledgements

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Funding

This study was supported by the National Natural Science Foundation of China, China (Grant No. 82171334), the Chongqing Science and Health Joint Medical Research Project, China (Grant No. 2023ZDXM016), and the Individualized training program for the excellent talent pool of the Army Medical University.

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  1. Wenchao Cheng, Yuhan Wang and Lan Zhang have contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, Xinqiao Hospital, The Army Medical University (Third Military Medical University), Chongqing, China

    Wenchao Cheng, Yuhan Wang, Lan Zhang, Chang Cheng & Wen Huang

  2. Department of Neurology, Chongqing Emergency Medical Center, Chongqing University Central Hospital, Chongqing University, Chongqing, China

    Xiuying Chen & Wen Huang

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  1. Wenchao Cheng
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Contributions

W.H. contributed to the conception and design of the study. W.C. and Y.W. organized the database and wrote the manuscript. W.C., Y.W. and L.Z. performed the statistical analysis. C.C. and X.C. participated in some experimental operations. All authors contributed to the manuscript revision and approved the submitted version.

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Correspondence to Wen Huang.

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The Laboratory Animal Welfare and Ethics Committee of Third Military Medical University sanctioned all animal operations, and all experiments were conducted following the applicable guidelines and regulations. Ethical Approval Number: AMUWEC20210276. Additionally, all methods are reported under ARRIVE guidelines for reporting animal experiments.

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Cheng, W., Wang, Y., Zhang, L. et al. The Impact of Dipyridamole on Disease-Associated Microglia Phenotypic Transformation in White Matter Lesions Induced by Chronic Cerebral Hypoperfusion. Neurochem Res 49, 744–757 (2024). https://doi.org/10.1007/s11064-023-04066-9

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