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Endocannabinoids modulate human blood-brain barrier permeability in vitro

Hind, William H.; Tufarelli, Cristina; Neophytou, Maria; Anderson, Susan I.; England, Timothy J.; O'Sullivan, Saoirse


William H. Hind

Cristina Tufarelli

Maria Neophytou

Susan I. Anderson

Timothy J. England

Saoirse O'Sullivan


Background and Purpose

Endocannabinoids alter permeability at various epithelial barriers, and cannabinoid receptors and endocannabinoid levels are elevated by stroke, with potential neuroprotective effects. We therefore explored the role of endocannabinoids in modulating blood–brain barrier (BBB) permeability in normal conditions and in an ischaemia/reperfusion model.
Experimental Approach

Human brain microvascular endothelial cell and astrocyte co-cultures modelled the BBB. Ischaemia was modelled by oxygen-glucose deprivation (OGD) and permeability was measured by transepithelial electrical resistance. Endocannabinoids or endocannabinoid-like compounds were assessed for their ability to modulate baseline permeability or OGD-induced hyperpermeability. Target sites of action were investigated using receptor antagonists and subsequently identified with real-time PCR.
Key Results

Anandamide (10 μM) and oleoylethanolamide (OEA, 10 μM) decreased BBB permeability (i.e. increased resistance). This was mediated by cannabinoid CB2 receptors, transient receptor potential vanilloid 1 (TRPV1) channels, calcitonin gene-regulated peptide (CGRP) receptor (anandamide only) and PPARα (OEA only). Application of OEA, palmitoylethanolamide (both PPARα mediated) or virodhamine (all 10 μM) decreased the OGD-induced increase in permeability during reperfusion. 2-Arachidonoyl glycerol, noladin ether and oleamide did not affect BBB permeability in normal or OGD conditions. N-arachidonoyl-dopamine increased permeability through a cytotoxic mechanism. PPARα and γ, CB1 receptors, TRPV1 channels and CGRP receptors were expressed in both cell types, but mRNA for CB2 receptors was only present in astrocytes.
Conclusion and Implication

The endocannabinoids may play an important modulatory role in normal BBB physiology, and also afford protection to the BBB during ischaemic stroke, through a number of target sites.


Hind, W. H., Tufarelli, C., Neophytou, M., Anderson, S. I., England, T. J., & O'Sullivan, S. (2015). Endocannabinoids modulate human blood-brain barrier permeability in vitro. British Journal of Pharmacology, 172(12), 3015-3027.

Journal Article Type Article
Acceptance Date Feb 1, 2015
Online Publication Date Apr 10, 2015
Publication Date Jun 1, 2015
Deposit Date Nov 1, 2016
Publicly Available Date Nov 1, 2016
Journal British Journal of Pharmacology
Print ISSN 0007-1188
Electronic ISSN 1476-5381
Publisher Wiley
Peer Reviewed Peer Reviewed
Volume 172
Issue 12
Pages 3015-3027
Public URL
Publisher URL


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