Cannabidiol protects an in vitro model of the blood-brain barrier from oxygen-glucose deprivation via PPARγ and 5-HT1A receptors.
OBJECTIVE
In vivo and in vitro studies have demonstrated a protective effect of cannabidiol (CBD) in reducing infarct size in stroke models and against epithelial barrier damage in numerous disease models. We aimed to investigate whether CBD also affects blood-brain barrier (BBB) permeability following ischaemia.


METHODS
Human brain microvascular endothelial cell (HBMEC) and human astrocyte co-cultures modelled the BBB. Ischaemia was modelled by oxygen-glucose deprivation (OGD) and permeability was measured by transepithelial electrical resistance.


RESULTS
CBD (10 μM) prevented the increase in permeability caused by 4 h OGD. CBD was most effective when administered before the OGD, but protective effects were observed up to 2 h into reperfusion. This protective effect was inhibited by a PPARγ antagonist and partly reduced by a 5-HT1A receptor antagonist, but was unaffected by antagonists of cannabinoid CB1 or CB2 receptors, TRPV1 channels or adenosine A2A receptors. CBD also reduced cell damage, as measured by LDH release and by markers of cellular adhesion, such as the adhesion molecule VCAM-1. In HBMEC monocultures, CBD decreased VCAM-1 and increased VEGF levels, effects which were inhibited by PPARγ antagonism.


CONCLUSIONS
These data suggest that preventing permeability changes at the BBB could represent an as yet unrecognized mechanism of CBD-induced neuroprotection in ischaemic stroke, a mechanism mediated by activation of PPARγ and 5-HT1A receptors.
School of Medicine, University of Nottingham, Royal Derby Hospital, Derby, UK.
William H
WH
Hind
School of Medicine, University of Nottingham, Royal Derby Hospital, Derby, UK.
Timothy J
TJ
England
School of Medicine, University of Nottingham, Royal Derby Hospital, Derby, UK.
Saoirse E
SE
O'Sullivan
D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D002545:Brain Ischemia / Q000378:metabolism; D002185:Cannabidiol / Q000494:pharmacology*; D015687:Cell Hypoxia; D002478:Cells, Cultured; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005947:Glucose / Q000172:deficiency; D006801:Humans; D018696:Neuroprotective Agents / Q000494:pharmacology*; D047495:PPAR gamma / Q000378:metabolism*; D010539:Permeability / Q000187:drug effects; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D018696:Neuroprotective Agents; D047495:PPAR gamma; C467484:VEGFA protein, human; D019010:Vascular Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; D044282:Receptor, Serotonin, 5-HT1A; D002185:Cannabidiol; D005947:Glucose