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Original Paper

Protective actions of des-acylated ghrelin on brain injury and blood–brain barrier disruption after stroke in mice

Jacqueline M. Ku, Mohammadali Taher, Kai Yee Chin, Tom Barsby, Victoria Austin, Connie H.Y. Wong, Zane B. Andrews, Sarah J. Spencer, Alyson A. Miller
Clinical Science Jul 26, 2016, 130 (17) 1545-1558; DOI: 10.1042/CS20160077
Jacqueline M. Ku
Cerebrovascular and Stroke Laboratory, School of Health and Biomedical Sciences, RMIT University, Melbourne, Victoria 3083, Australia
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Mohammadali Taher
Cerebrovascular and Stroke Laboratory, School of Health and Biomedical Sciences, RMIT University, Melbourne, Victoria 3083, Australia
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Kai Yee Chin
Cerebrovascular and Stroke Laboratory, School of Health and Biomedical Sciences, RMIT University, Melbourne, Victoria 3083, Australia
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Tom Barsby
Cerebrovascular and Stroke Laboratory, School of Health and Biomedical Sciences, RMIT University, Melbourne, Victoria 3083, Australia
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Victoria Austin
Cerebrovascular and Stroke Laboratory, School of Health and Biomedical Sciences, RMIT University, Melbourne, Victoria 3083, Australia
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Connie H.Y. Wong
Centre for Inflammatory Diseases, Department of Medicine, Monash Medical Centre, Monash University, Melbourne, Victoria 3168, Australia
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Zane B. Andrews
Department of Physiology, Monash University, Melbourne, Victoria 3800, Australia
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Sarah J. Spencer
Cerebrovascular and Stroke Laboratory, School of Health and Biomedical Sciences, RMIT University, Melbourne, Victoria 3083, Australia
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Alyson A. Miller
Cerebrovascular and Stroke Laboratory, School of Health and Biomedical Sciences, RMIT University, Melbourne, Victoria 3083, Australia
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  • For correspondence: alyson.miller@rmit.edu.au
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Abstract

The major ghrelin forms, acylated ghrelin and des-acylated ghrelin, are novel gastrointestinal hormones. Moreover, emerging evidence indicates that these peptides may have other functions including neuro- and vaso-protection. Here, we investigated whether post-stroke treatment with acylated ghrelin or des-acylated ghrelin could improve functional and histological endpoints of stroke outcome in mice after transient middle cerebral artery occlusion (tMCAo). We found that des-acylated ghrelin (1 mg/kg) improved neurological and functional performance, reduced infarct and swelling, and decreased apoptosis. In addition, it reduced blood-brain barrier (BBB) disruption in vivo and attenuated the hyper-permeability of mouse cerebral microvascular endothelial cells after oxygen glucose deprivation and reoxygenation (OGD + RO). By contrast, acylated ghrelin (1 mg/kg or 5 mg/kg) had no significant effect on these endpoints of stroke outcome. Next we found that des-acylated ghrelin's vasoprotective actions were associated with increased expression of tight junction proteins (occludin and claudin-5), and decreased cell death. Moreover, it attenuated superoxide production, Nox activity and expression of 3-nitrotyrosine. Collectively, these results demonstrate that post-stroke treatment with des-acylated ghrelin, but not acylated ghrelin, protects against ischaemia/reperfusion-induced brain injury and swelling, and BBB disruption, by reducing oxidative and/or nitrosative damage.

  • blood–brain barrier
  • ghrelin
  • ischaemia
  • neuroprotection
  • reperfusion
  • Abbreviations

    BBB,
    blood–brain barrier;
    DMEM,
    Dulbecco's modified Eagle's medium;
    GHSR1a,
    growth hormone secretagogue receptor 1a;
    GOAT,
    ghrelin O-acyltransferase;
    OGD,
    oxygen glucose deprivation;
    rCBF,
    regional cerebral blood flow;
    RNS,
    reactive nitrogen species;
    RO,
    reoxygenation;
    ROS,
    reactive oxygen species;
    RT,
    reverse transcription;
    rt-PA,
    recombinant tissue plasminogen activator;
    SOD,
    superoxide dismutase;
    tMCAo,
    transient middle cerebral artery occlusion;
    TUNEL,
    terminal deoxynucleotidyltransferase-mediated dUTP nick-end labelling;
    ZO-1,
    zonula occludens 1
    • © 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society
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    September 2016

    Volume: 130 Issue: 17

    Clinical Science: 130 (17)
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    Protective actions of des-acylated ghrelin on brain injury and blood–brain barrier disruption after stroke in mice
    Jacqueline M. Ku, Mohammadali Taher, Kai Yee Chin, Tom Barsby, Victoria Austin, Connie H.Y. Wong, Zane B. Andrews, Sarah J. Spencer, Alyson A. Miller
    Clinical Science Sep 2016, 130 (17) 1545-1558; DOI: 10.1042/CS20160077
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    Protective actions of des-acylated ghrelin on brain injury and blood–brain barrier disruption after stroke in mice
    Jacqueline M. Ku, Mohammadali Taher, Kai Yee Chin, Tom Barsby, Victoria Austin, Connie H.Y. Wong, Zane B. Andrews, Sarah J. Spencer, Alyson A. Miller
    Clinical Science Sep 2016, 130 (17) 1545-1558; DOI: 10.1042/CS20160077

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    Keywords

    blood–brain barrier
    ghrelin
    ischaemia
    neuroprotection
    reperfusion

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