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Edaravone Maintains AQP4 Polarity Via OS/MMP9/β-DG Pathway in an Experimental Intracerebral Hemorrhage Mouse Model

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Abstract

Oxidative stress (OS) is the main cause of secondary damage following intracerebral hemorrhage (ICH). The polarity expression of aquaporin-4 (AQP4) has been shown to be important in maintaining the homeostasis of water transport and preventing post-injury brain edema in various neurological disorders. This study primarily aimed to investigate the effect of the oxygen free radical scavenger, edaravone, on AQP4 polarity expression in an ICH mouse model and determine whether it involves in AQP4 polarity expression via the OS/MMP9/β-dystroglycan (β-DG) pathway. The ICH mouse model was established by autologous blood injection into the basal nucleus. Edaravone or the specific inhibitor of matrix metalloproteinase 9 (MMP9), MMP9-IN-1, called MMP9-inh was administered 10 min after ICH via intraperitoneal injection. ELISA detection, neurobehavioral tests, dihydroethidium staining (DHE staining), intracisternal tracer infusion, hematoxylin and eosin (HE) staining, immunofluorescence staining, western blotting, Evans blue (EB) permeability assay, and brain water content test were performed. The results showed that OS was exacerbated, AQP4 polarity was lost, drainage function of brain fluids was damaged, brain injury was aggravated, expression of AQP4, MMP9, and GFAP increased, while the expression of β-DG decreased after ICH. Edaravone reduced OS, restored brain drainage function, reduced brain injury, and downregulated the expression of AQP4, MMP9. Both edaravone and MMP9-inh alleviated brain edema, maintained blood–brain barrier (BBB) integrity, mitigated the loss of AQP4 polarity, downregulated GFAP expression, and upregulated β-DG expression. The current study suggests that edaravone can maintain AQP4 polarity expression by inhibiting the OS /MMP9/β-DG pathway after ICH.

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Data Availability

The datasets used and/or analyzed in the current study are available from the corresponding authors on request.

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Funding

This work was supported by the National Natural Science Foundation of China (NSFC 82171457), Natural Science Foundation of Chongqing (CSTB2022NSCQ-MSX1083), and Program for Youth Innovation in Future Medicine, Chongqing Medical University (W0031).

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  1. Zhenhua Wang, Yuan Li, and Zhixu Wang contributed equally to this work.

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  1. Department of Anatomy, Basic Medical College, Chongqing Medical University, Chongqing, China

    Zhenhua Wang, Yuan Li, Zhixu Wang, Yuhui Liao, Qingqing Ye, Shilong Tang, Ting Wei, Pengyu Xiao, Juan Huang & Weitian Lu

  2. Institute of Neuroscience, Basic Medical College, Chongqing Medical University, Chongqing, China

    Zhenhua Wang, Yuan Li, Zhixu Wang, Yuhui Liao, Qingqing Ye, Shilong Tang, Ting Wei, Pengyu Xiao, Juan Huang & Weitian Lu

  3. Sichuan University of Arts and Science, Sichuan, China

    Yuhui Liao

  4. Department of Radiology, Children’s Hospital of Chongqing Medical University, Chongqing, China

    Shilong Tang

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All authors contributed to the conception and design of the study. Material preparation, data collection, and analysis were performed by Zhenhua Wang, Yuan Li, and Zhixu Wang. The initial draft of the manuscript was written by Zhenghua Wang, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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This project involves the purchase of animals from the Animal Center of Chongqing Medical University. The experimental protocol has been reviewed by the Institutional Animal Care and Use Committee of Chongqing Medical University (IACUC-CQMU) and is in accordance with principles of animal protection, animal welfare, and ethics. It complies with relevant regulations on the welfare and ethics of experimental animals in the country (Approval No: IACUC-CQMU-2023–0117).

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Wang, Z., Li, Y., Wang, Z. et al. Edaravone Maintains AQP4 Polarity Via OS/MMP9/β-DG Pathway in an Experimental Intracerebral Hemorrhage Mouse Model. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-04028-4

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