Abstract
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 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 via RT-PCR.
KEY RESULTS:
Anandamide (10μM, P<0.05) and oleoylethanolamide (OEA, 10μM, P<0.01) decreased BBB permeability (i.e. increased resistance). This was mediated by CB2 , transient receptor potential vanilloid 1 (TRPV1), the calcitonin gene regulated peptide (CGRP) receptor (anandamide only) and peroxisome proliferator activated receptor (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 , TRPV1, and CGRP receptor expression was shown in both cell types, but CB2 mRNA was only present in astrocytes.
CONCLUSION AND IMPLICATION:
These data show that 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.
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- PMID:
- 25651941
- [PubMed – as supplied by publisher]
