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Open Access Research

Anandamide inhibits Theiler's virus induced VCAM-1 in brain endothelial cells and reduces leukocyte transmigration in a model of blood brain barrier by activation of CB1 receptors

Leyre Mestre1, Paula M Iñigo1, Miriam Mecha1, Fernando G Correa12, Miriam Hernangómez-Herrero1, Frida Loría1, Fabian Docagne13, José Borrell1 and Carmen Guaza1*

Author Affiliations

1 Neuroimmunology Group, Functional and Systems Neurobiology Department, Cajal Institute, CSIC, 28002 Madrid, Spain

2 Department of Medical Biochemistry and Cellular Biology, Institute for Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden

3 INSERM, INSERM U919 'Serine Proteases and Pathophysiology of the Neurovascular Unit', GIP Cyceron, Caen Cedex, France

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Journal of Neuroinflammation 2011, 8:102  doi:10.1186/1742-2094-8-102

Published: 18 August 2011

Abstract

Background

VCAM-1 represents one of the most important adhesion molecule involved in the transmigration of blood leukocytes across the blood-brain barrier (BBB) that is an essential step in the pathogenesis of MS. Several evidences have suggested the potential therapeutic value of cannabinoids (CBs) in the treatment of MS and their experimental models. However, the effects of endocannabinoids on VCAM-1 regulation are poorly understood. In the present study we investigated the effects of anandamide (AEA) in the regulation of VCAM-1 expression induced by Theiler's virus (TMEV) infection of brain endothelial cells using in vitro and in vivo approaches.

Methods

i) in vitro: VCAM-1 was measured by ELISA in supernatants of brain endothelial cells infected with TMEV and subjected to AEA and/or cannabinoid receptors antagonist treatment. To evaluate the functional effect of VCAM-1 modulation we developed a blood brain barrier model based on a system of astrocytes and brain endothelial cells co-culture. ii) in vivo: CB1 receptor deficient mice (Cnr1-/-) infected with TMEV were treated with the AEA uptake inhibitor UCM-707 for three days. VCAM-1 expression and microglial reactivity were evaluated by immunohistochemistry.

Results

Anandamide-induced inhibition of VCAM-1 expression in brain endothelial cell cultures was mediated by activation of CB1 receptors. The study of leukocyte transmigration confirmed the functional relevance of VCAM-1 inhibition by AEA. In vivo approaches also showed that the inhibition of AEA uptake reduced the expression of brain VCAM-1 in response to TMEV infection. Although a decreased expression of VCAM-1 by UCM-707 was observed in both, wild type and CB1 receptor deficient mice (Cnr1-/-), the magnitude of VCAM-1 inhibition was significantly higher in the wild type mice. Interestingly, Cnr1-/- mice showed enhanced microglial reactivity and VCAM-1 expression following TMEV infection, indicating that the lack of CB1 receptor exacerbated neuroinflammation.

Conclusions

Our results suggest that CB1 receptor dependent VCAM-1 inhibition is a novel mechanism for AEA-reduced leukocyte transmigration and contribute to a better understanding of the mechanisms underlying the beneficial role of endocannabinoid system in the Theiler's virus model of MS.

Keywords:
Endocannabinoids; VCAM-1; Blood brain barrier, TMEV; Multiple Sclerosis