Protective actions of des-acylated ghrelin on brain injury and blood-brain barrier disruption after stroke in mice.
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.
Cerebrovascular and Stroke Laboratory, School of Health and Biomedical Sciences, RMIT University, Melbourne, Victoria 3083, Australia.
Jacqueline M
JM
Ku
Cerebrovascular and Stroke Laboratory, School of Health and Biomedical Sciences, RMIT University, Melbourne, Victoria 3083, Australia.
Mohammadali
M
Taher
Cerebrovascular and Stroke Laboratory, School of Health and Biomedical Sciences, RMIT University, Melbourne, Victoria 3083, Australia.
Kai Yee
KY
Chin
Cerebrovascular and Stroke Laboratory, School of Health and Biomedical Sciences, RMIT University, Melbourne, Victoria 3083, Australia.
Tom
T
Barsby
Cerebrovascular and Stroke Laboratory, School of Health and Biomedical Sciences, RMIT University, Melbourne, Victoria 3083, Australia.
Victoria
V
Austin
Centre for Inflammatory Diseases, Department of Medicine, Monash Medical Centre, Monash University, Melbourne, Victoria 3168, Australia.
Connie H Y
CH
Wong
Department of Physiology, Monash University, Melbourne, Victoria 3800, Australia.
Zane B
ZB
Andrews
Cerebrovascular and Stroke Laboratory, School of Health and Biomedical Sciences, RMIT University, Melbourne, Victoria 3083, Australia.
Sarah J
SJ
Spencer
Cerebrovascular and Stroke Laboratory, School of Health and Biomedical Sciences, RMIT University, Melbourne, Victoria 3083, Australia alyson.miller@rmit.edu.au.
Alyson A
AA
Miller
D000215:Acylation; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001930:Brain Injuries / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism; D054439:Ghrelin / Q000008:administration & dosage / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010100:Oxygen / Q000378:metabolism; D020011:Protective Agents / Q000008:administration & dosage / Q000378:metabolism*; D020521:Stroke / Q000150:complications*
D054439:Ghrelin; D020011:Protective Agents; D010100:Oxygen
blood–brain barrier; ghrelin; ischaemia; neuroprotection; reperfusion