A role for cannabinoids in the regulation of adhesion molecules in brain endothelium

Leyre Mestre, Fabian Docagne, Fernando Correa, Diego Clemente, Frida Loría, Miriam Hernangómez, José Borrell, Carmen Guaza. Cajal Institute (CSIC), Madrid, Spain.

Alterations of the central nervous system (CNS) microvascular endothelium are closely linked to the pathogenesis of several neuroinflammatory diseases. Adhesion molecules are involved in the leukocyte recruitment at the blood brain barrier. Theiler’s virus infection of the CNS induces an immune-mediated demyelinating disease (TMEV-IDD) in susceptible mouse strains and serves as a relevant infection model for human multiple sclerosis (MS). Our previous work showed that administration of cannabinoids or the pharmacological activation of endocannabinoid tone ameliorates motor deficits, diminishes leukocyte infiltration and reduces microglial reactivity (Arévalo-Martín et. al, 2003; Mestre et al., 2005). In the present study we investigated whether cannabinoids regulate the expression of adhesion molecules in brain endothelial cells. In particular, we studied the effects of the synthetic cannabinoid agonist WIN 55,212-2 in the expression of intercellular adhesion molecule-1 (ICAM)-1 and vascular cell adhesion molecule-1 (VCAM-1) in brain endothelial murine cell cultures infected with TMEV.

Our data show that TMEV infection increases VCAM-1 expression (158 ± 13 % vs. Control) and modify ICAM-1 protein in brain endothelial cells. In addition, WIN 55,212-2 inhibits the above effects by a mechanism independent on CB1 and CB2 activation (p<0.01). Interestingly, PI3K, p38 MAPK and p42/44 MAPK pathways inhibitors diminish VCAM-1 expression TMEV-induced (∼50%) in WIN 55,212-2 brain endothelial cells treated. Moreover, anandamide was capable of diminishing (98 ± 2 %) TMEV-induced VCAM-1 by CB1 receptor on this type of cells (p<0.01). Astrocytes from FAAH-/- show a reduction of VCAM-1 induction (p<0.01).

Overall our results suggest that cannabinoids by targeting brain endothelium may affect the development of CNS pathologies related to neuroinflammation like multiple sclerosis.

Acknowledgements: We gratefully appreciated Dr. Moses Rodriguez (Department of Immunology and Neurology, Mayo Clinic/Foundation, Rochester, Minnesota, USA) for provision of Theiler’s virus DA strain.

Arévalo-Martín et al. (2003). J Neurosci. 23: 2511-2516

Mestre L et al. (2005) J. Neurochem. 92: 1327-1339

Supported by grants from MCYT (SAF-2004/0416)