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Recombinant Adiponectin Peptide Ameliorates Brain Injury Following Intracerebral Hemorrhage by Suppressing Astrocyte-Derived Inflammation via the Inhibition of Drp1-Mediated Mitochondrial Fission

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Abstract

Intracerebral hemorrhage (ICH) is a life-threatening subtype of cerebral stroke with high morbidity and mortality; however, effective treatment for ICH is still lacking. Adiponectin (APN) is a a kind of fat-derived plasma protein with beneficial effects in cerebrovascular disorders. In this study, we aimed to investigate the protective effects of recombinant APN peptide (APNp) on brain injury after ICH in adult male C57BL/6J mice and further explored the underlying molecular mechanisms of these effects. APNp treatment exerted dose-dependent neuroprotective effects including improved neurological function, decreased brain edema, reduced neural apoptosis, and alleviated blood–brain barrier (BBB) disruption in ICH mice. We found the massive accumulation of APNp on reactive astrocytes around brain microvessels under hemorrhage conditions by immunofluorescence analysis. mRNA sequencing (mRNA-seq) and transcriptome analysis indicated that APNp significantly attenuated the inflammatory response and mitochondrial respiratory dysfunction in astrocytes. Further study revealed that this process was, at least in part, reliant on the inhibition of Drp1-mediated excessive mitochondrial fission. More specifically, APNp increased AMP-activated protein kinase (AMPK) activation-dependent Drp1 serine 637 (S637) phosphorylation, which inhibited the translocation of Drp1 to the mitochondrial membrane and reduced mitochondrial fragmentation and the production of mitochondrial superoxide, ultimately attenuating inflammatory brain injury induced by hemorrhage. In conclusion, we propose APNp as a potential therapeutic agent for ICH. We provide the first mechanistic evidence that APNp can modulate Drp1-mediated mitochondrial fission, which then contributes to alleviating astrocyte-derived inflammation.

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Funding

This work was supported by grants from the State Key Program of the National Natural Science Foundation of China (81630027, to Dr. Qu), the National Natural Science Foundation of China (81571215, to Dr. Qu), and the Chang Jiang Scholar Program of China (to Dr. Qu).

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  1. Xun Wu, Jianing Luo and Haixiao Liu contributed equally to this work.

Authors and Affiliations

  1. Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xi’an, 710038, Shaanxi, China

    Xun Wu, Jianing Luo, Haixiao Liu, Wenxing Cui, Kang Guo, Lei Zhao, Hao Bai, Wei Guo, Hao Guo, Dayun Feng & Yan Qu

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  1. Xun Wu
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Contributions

Y. Q. and D-Y. F. carried out this project and designed the study. X. W. performed the animal experiments, J-N. L. and H-X. L. performed the in vitro experiments, and W-X. C. and K. G. carried out statistical analysis and interpreted the data. L. Z. and H. B. helped in drafting the manuscript. H. G. and W. G. revised the manuscript. Thanks to Liang Jialong who help us to stimulate the structure diagram of APNp with Discovery Studio V16.1 software

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Correspondence to Dayun Feng or Yan Qu.

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All experimental procedures described here were approved by the Ethics Committee of the Fourth Military Medical University and performed in accordance with the guidelines of the National Institutes of Health Guide for the Care and Use of Laboratory Animals.

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Wu, X., Luo, J., Liu, H. et al. Recombinant Adiponectin Peptide Ameliorates Brain Injury Following Intracerebral Hemorrhage by Suppressing Astrocyte-Derived Inflammation via the Inhibition of Drp1-Mediated Mitochondrial Fission. Transl. Stroke Res. 11, 924–939 (2020). https://doi.org/10.1007/s12975-019-00768-x

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