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 MESTRE, FERNANDO CORREA, MIRIAM HERNANGÓMEZ-HERRERO, FRIDA LORÍA, MIRIAM MECHA, PAULA M IÑIGO, FABIAN DOCAGNE AND CARMEN GUAZA

JOURNAL OF NEUROINFLAMMATION

BIOMED CENTRAL LTD

Año: 2011 vol. 8 p. 1 - 13

1742-2094

The leucocyte entry into the central nervous system through the blood brain barrier (BBB) is among the earliest event in multiple sclerosis, with the particular involvement of adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1). Cumulative evidence indicates that the endocannabinoid system is dysregulated in multiple sclerosis and its pharmacological manipulation might be a potential therapeutic strategy for the treatment of this disease. In the present study we investigated the effects of anandamide 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. Anandamide-induced inhibition of VCAM-1 expression in brain endothelial cell cultures involved at least in part, the activation of CB1 receptors although the contribution of alternative mechanisms can not be ruled out. The functional relevance of VCAM-1 inhibition by anandamide was confirmed using an in vitro BBB model. In vivo approaches reveal that the anandamide uptake inhibition by UCM707 inhibits the early brain VCAM-1 responses induced by TMEV in both CB1 receptor deficient mice (Cnr1-/-) and in wild type, suggesting that potential non CB1-mechanisms may exist. Interestingly, Cnr1-/- mice showed a significant increase in glial reactivity (both microglia and astrocytes) in response to TMEV infection, indicating that the lack of CB1 receptor exacerbates neuroinflammation. Taken together the above findings contribute to a better understanding of the events underlying beneficial role of endocannabinoids by limiting leukocyte infiltration into CNS in the Theiler’s virus model of MS.