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Endocannabinoids modulate human blood–brain barrier permeability in vitro
Author(s) -
Hind William H,
Tufarelli Cristina,
Neophytou Maria,
Anderson Susan I,
England Timothy J,
O'Sullivan Saoirse E
Publication year - 2015
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13106
Subject(s) - endocannabinoid system , cannabinoid receptor , trpv1 , anandamide , cannabinoid , cannabinoid receptor type 2 , chemistry , pharmacology , receptor , neuroprotection , blood–brain barrier , biology , endocrinology , medicine , transient receptor potential channel , biochemistry , agonist , central nervous system
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 CB 2 receptors, transient receptor potential vanilloid 1 ( TRPV 1) channels, calcitonin gene‐regulated peptide ( CGRP ) receptor (anandamide only) and PPARα ( OEA only). Application of OEA , palmitoylethanolamide (both PPAR α 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. PPAR α and γ, CB 1 receptors, TRPV 1 channels and CGRP receptors were expressed in both cell types, but mRNA for CB 2 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.