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