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Digoxin Ameliorates Glymphatic Transport and Cognitive Impairment in a Mouse Model of Chronic Cerebral Hypoperfusion

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Abstract

The glymphatic system plays a pivotal role in maintaining cerebral homeostasis. Chronic cerebral hypoperfusion, arising from small vessel disease or carotid stenosis, results in cerebrometabolic disturbances ultimately manifesting in white matter injury and cognitive dysfunction. However, whether the glymphatic system serves as a potential therapeutic target for white matter injury and cognitive decline during hypoperfusion remains unknown. Here, we established a mouse model of chronic cerebral hypoperfusion via bilateral common carotid artery stenosis. We found that the hypoperfusion model was associated with significant white matter injury and initial cognitive impairment in conjunction with impaired glymphatic system function. The glymphatic dysfunction was associated with altered cerebral perfusion and loss of aquaporin 4 polarization. Treatment of digoxin rescued changes in glymphatic transport, white matter structure, and cognitive function. Suppression of glymphatic functions by treatment with the AQP4 inhibitor TGN-020 abolished this protective effect of digoxin from hypoperfusion injury. Our research yields new insight into the relationship between hemodynamics, glymphatic transport, white matter injury, and cognitive changes after chronic cerebral hypoperfusion.

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Acknowledgments

This work was supported by Grants from the National Natural Science Foundation of China (81873749 and 81801072). We sincerely thank the Optical Bioimaging Core Facility of Wuhan Laboratory for Optoelectronics–Hong Kong University of Science and Technology for support in data acquisition, Dr. P. Liu for helpful discussions during data acquisition, and Prof. Paul Cumming for manuscript review.

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  1. Jie Cao and Di Yao contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Jie Cao, Di Yao, Rong Li, Xuequn Guo, Jiahuan Hao, Minjie Xie, Jia Li, Dengji Pan, Xiang Luo, Zhiyuan Yu, Minghuan Wang & Wei Wang

  2. Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Rong Li

  3. Department of Respiratory Medicine, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, 362000, China

    Xuequn Guo

  4. Key Laboratory of Neurological Diseases of the Chinese Ministry of Education, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Wei Wang

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  1. Jie Cao
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Correspondence to Minghuan Wang or Wei Wang.

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Cao, J., Yao, D., Li, R. et al. Digoxin Ameliorates Glymphatic Transport and Cognitive Impairment in a Mouse Model of Chronic Cerebral Hypoperfusion. Neurosci. Bull. 38, 181–199 (2022). https://doi.org/10.1007/s12264-021-00772-y

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