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

Abstract

. (2016) Protective actions of des-acylated ghrelin on brain injury and blood-brain barrier disruption after stroke in mice. Clinical Science, 130(17), pp. 1545-1558. (doi:10.1042 This is the author's final accepted version.There may be differences between this version and the published version. You are advised to consult the publisher's version if you wish to cite from it.http://eprints.gla.ac.uk/135040/ AbstractThe 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. 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 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 poststroke treatment with des-acylated ghrelin, but not acylated ghrelin, protects against ischemia/reperfusion-induced brain injury and swelling, and BBB disruption by reducing oxidative and/or nitrosative damage. Summary statementStroke is a leading cause of death, but treatments are limited. This experimental study reveals that the hormone ghrelin powerfully protects the brain and its blood vessels against injury after stroke, raising the possibility that it could be exploited therapeutically. Short titleDes-acylated ghrelin protects against stroke. KeywordsIschemia, reperfusion, ghrelin, neuroprotection, blood-brain barrier. Abbreviations listBlood-brain barrier (BBB); ghrelin O-acyltransferase (GOAT); growth hormone secretagogue receptor 1a (GHSR1a); oxygen glucose deprivation and reoxygenation (OGD + Clinical perspectives• Ischemic stroke is a leading cause of mortality and long-term disability, but treatment options are limited. The major ghrelin forms, acylated ghrelin and des-acylated ghrelin, are novel gastrointestinal hormones. Moreover, recent evidence indicates these peptides may have neuroprotective and vasoprotective actions, and thus may protective actions in ischemic stroke.• In this study we tested whether the peptides could mediate protection in a clinically relevant mouse model of ischemic stroke.• Our findings reveal protective actions of des-acylated ghrelin whe...

Antiretroviral Treatment with Efavirenz Disrupts the Blood-Brain Barrier Integrity and Increases Stroke Severity

“…Claudin-5 was demonstrated to be an important contributor to BBB integrity61 and its upregulation correlates with a protective effect against CNS tissue injury62. Similar observations have been made for ZO-1 and occludin both in vitro and in vivo 62636465. In our model system, exposure to Efavirenz selectively decreased the levels of claudin-5.…”

“…The barrier function is highly reliant on the formation of TJs, composed especially claudin-5, ZO-1, and occludin, which were included in the present study. Claudin-5 was demonstrated to be an important contributor to BBB integrity61 and its upregulation correlates with a protective effect against CNS tissue injury62. Similar observations have been made for ZO-1 and occludin both in vitro and in vivo 62636465.…”

Ghrelin protects adult rat hippocampal neural stem cells from excessive autophagy during oxygen-glucose deprivation

“…In addition, ghrelin has been recently been shown to have, including CNS to control neuronal function [26] and various brain injury [27,28]. Several growth factors, including bFGF and insulin like growth factor have been implicated in neuroprotective effect.…”

Involvement of Astrocytes in Mediating the Central Effects of Ghrelin

“…It is proposed that ghrelin could act through an uncoupling protein 2 (UCP-2)-mediated mechanism to attenuate BBB disruption during injury [148]. In contrast, in response to stroke desacyl- but not acyl-ghrelin is reported to improve both functional and neurological outcomes after cerebral artery occlusion [149]. In this study, post-stroke treatment with desacyl-ghrelin decreased the infarct area and swelling and reduced BBB disruption [149].…”

“…In contrast, in response to stroke desacyl- but not acyl-ghrelin is reported to improve both functional and neurological outcomes after cerebral artery occlusion [149]. In this study, post-stroke treatment with desacyl-ghrelin decreased the infarct area and swelling and reduced BBB disruption [149]. These two isoforms could perform beneficial effects through different mechanisms and thus be more or less effective in activating protection processes depending on the type of injury, although this remains to be demonstrated.…”