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 CB(1) Receptors

Overview

Journal J Neuroinflammation

Publisher Biomed Central

Date 2011 Aug 20

PMID 21851608

Citations 28

Authors

Leyre Mestre

Paula M Inigo

Miriam Mecha

Fernando G Correa

Miriam Hernangomez-Herrero

Frida Loria

Fabian Docagne

Jose Borrell

Carmen Guaza

Affiliations

Soon will be listed here.

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: CB(1) 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 CB(1) 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 CB(1) 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 CB(1) receptor exacerbated neuroinflammation.

Conclusions: Our results suggest that CB(1) 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.

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References

Craig L, Spelman J, Strandberg J, Zink M . Endothelial cells from diverse tissues exhibit differences in growth and morphology. Microvasc Res. 1998; 55(1):65-76. DOI: 10.1006/mvre.1997.2045. View

Benito C, Romero J, Tolon R, Clemente D, Docagne F, Hillard C . Cannabinoid CB1 and CB2 receptors and fatty acid amide hydrolase are specific markers of plaque cell subtypes in human multiple sclerosis. J Neurosci. 2007; 27(9):2396-402. PMC: 6673484. DOI: 10.1523/JNEUROSCI.4814-06.2007. View

Molina-Holgado E, Molina-Holgado F . Mending the broken brain: neuroimmune interactions in neurogenesis. J Neurochem. 2010; 114(5):1277-90. DOI: 10.1111/j.1471-4159.2010.06849.x. View

Millonig A, Hegen H, Di Pauli F, Ehling R, Gneiss C, Hoelzl M . Natalizumab treatment reduces endothelial activity in MS patients. J Neuroimmunol. 2010; 227(1-2):190-4. DOI: 10.1016/j.jneuroim.2010.07.012. View

Mestre L, Docagne F, Correa F, Loria F, Hernangomez M, Borrell J . A cannabinoid agonist interferes with the progression of a chronic model of multiple sclerosis by downregulating adhesion molecules. Mol Cell Neurosci. 2008; 40(2):258-66. DOI: 10.1016/j.mcn.2008.10.015. View

Ortega-Gutierrez S, Molina-Holgado E, Arevalo-Martin A, Correa F, Viso A, Lopez-Rodriguez M . Activation of the endocannabinoid system as therapeutic approach in a murine model of multiple sclerosis. FASEB J. 2005; 19(10):1338-40. DOI: 10.1096/fj.04-2464fje. View

Rossi S, Buttari F, Studer V, Motta C, Gravina P, Castelli M . The (AAT)n repeat of the cannabinoid CB1 receptor gene influences disease progression in relapsing multiple sclerosis. Mult Scler. 2010; 17(3):281-8. DOI: 10.1177/1352458510388680. View

Gaillard P, Voorwinden L, Nielsen J, Ivanov A, Atsumi R, Engman H . Establishment and functional characterization of an in vitro model of the blood-brain barrier, comprising a co-culture of brain capillary endothelial cells and astrocytes. Eur J Pharm Sci. 2000; 12(3):215-22. DOI: 10.1016/s0928-0987(00)00123-8. View

Ukkonen M, Wu K, Reipert B, Dastidar P, Elovaara I . Cell surface adhesion molecules and cytokine profiles in primary progressive multiple sclerosis. Mult Scler. 2007; 13(6):701-7. DOI: 10.1177/1352458506075378. View

10.

Mestre L, Correa F, Docagne F, Clemente D, Guaza C . The synthetic cannabinoid WIN 55,212-2 increases COX-2 expression and PGE2 release in murine brain-derived endothelial cells following Theiler's virus infection. Biochem Pharmacol. 2006; 72(7):869-80. DOI: 10.1016/j.bcp.2006.06.037. View

11.

Yiangou Y, Facer P, Durrenberger P, Chessell I, Naylor A, Bountra C . COX-2, CB2 and P2X7-immunoreactivities are increased in activated microglial cells/macrophages of multiple sclerosis and amyotrophic lateral sclerosis spinal cord. BMC Neurol. 2006; 6:12. PMC: 1413551. DOI: 10.1186/1471-2377-6-12. View

12.

Chen P, Hu S, Yao J, Moore S, Spector A, Fang X . Induction of cyclooxygenase-2 by anandamide in cerebral microvascular endothelium. Microvasc Res. 2005; 69(1-2):28-35. DOI: 10.1016/j.mvr.2005.02.001. View

13.

Centonze D, Bari M, Rossi S, Prosperetti C, Furlan R, Fezza F . The endocannabinoid system is dysregulated in multiple sclerosis and in experimental autoimmune encephalomyelitis. Brain. 2007; 130(Pt 10):2543-53. DOI: 10.1093/brain/awm160. View

14.

Lu T, Avraham H, Seng S, Tachado S, Koziel H, Makriyannis A . Cannabinoids inhibit HIV-1 Gp120-mediated insults in brain microvascular endothelial cells. J Immunol. 2008; 181(9):6406-16. PMC: 3735224. DOI: 10.4049/jimmunol.181.9.6406. View

15.

Cabranes A, Venderova K, de Lago E, Fezza F, Sanchez A, Mestre L . Decreased endocannabinoid levels in the brain and beneficial effects of agents activating cannabinoid and/or vanilloid receptors in a rat model of multiple sclerosis. Neurobiol Dis. 2005; 20(2):207-17. DOI: 10.1016/j.nbd.2005.03.002. View

16.

Panikashvili D, Shein N, Mechoulam R, Trembovler V, Kohen R, Alexandrovich A . The endocannabinoid 2-AG protects the blood-brain barrier after closed head injury and inhibits mRNA expression of proinflammatory cytokines. Neurobiol Dis. 2005; 22(2):257-64. DOI: 10.1016/j.nbd.2005.11.004. View

17.

Golech S, McCarron R, Chen Y, Bembry J, Lenz F, Mechoulam R . Human brain endothelium: coexpression and function of vanilloid and endocannabinoid receptors. Brain Res Mol Brain Res. 2004; 132(1):87-92. DOI: 10.1016/j.molbrainres.2004.08.025. View

18.

Stella N . Endocannabinoid signaling in microglial cells. Neuropharmacology. 2008; 56 Suppl 1:244-53. PMC: 2654419. DOI: 10.1016/j.neuropharm.2008.07.037. View

19.

Wagner J, Hu K, Karcher J, Bauersachs J, Schafer A, Laser M . CB(1) cannabinoid receptor antagonism promotes remodeling and cannabinoid treatment prevents endothelial dysfunction and hypotension in rats with myocardial infarction. Br J Pharmacol. 2003; 138(7):1251-8. PMC: 1573770. DOI: 10.1038/sj.bjp.0705156. View

20.

Correa F, Hernangomez-Herrero M, Mestre L, Loria F, Docagne F, Guaza C . The endocannabinoid anandamide downregulates IL-23 and IL-12 subunits in a viral model of multiple sclerosis: evidence for a cross-talk between IL-12p70/IL-23 axis and IL-10 in microglial cells. Brain Behav Immun. 2011; 25(4):736-49. DOI: 10.1016/j.bbi.2011.01.020. View