Cannabidiol provides long-lasting protection against the deleterious effects of inflammation in a viral model of multiple sclerosis : A role for A2A receptors
Neurobiology of Disease, 2013, 59, 141–150
Inflammation in the central nervous system (CNS) is a complex process that involves a multitude of mole-cules and effectors, and it requires the transmigration of blood leukocytes across the blood–brain barrier(BBB) and the activation of resident immune cells. Cannabidiol (CBD), a non-psychotropic cannabinoid constituent of Cannabis sativa, has potent anti-inflammatory and immunosuppressive properties. Yet, how this compound modifies the deleterious effects of inflammation in TMEV-induced demyelinating disease (TMEV-IDD) remains unknown. Using this viral model of multiple sclerosis (MS), we demonstrate that CBD decreases the transmigration of blood leukocytes by downregulating the expression of vascular cell adhesionmolecule-1 (VCAM-1), chemokines (CCL2 and CCL5) and the proinflammatory cytokine IL-1β,as well as by attenuating the activation of microglia. Moreover, CBD administration at the time of viral infection exerts long-lasting effects, ameliorating motor deficits in the chronic phase of the disease in conjunction with reduced microglial activation and pro-inflammatory cytokine production. Adenosine A2Areceptors participate in some ofthe anti-inflammatory effects of CBD, as the A2Aantagonist ZM241385 partially blocks the protective effects of CBD in the initial stages of inflammation. Together, our findings highlight the anti-inflammatory effects of CBD in this viral model of MS and demonstrate the significant therapeutic potential of this compound for the treatment of pathologies with an inflammatory component.
Keywords : Cannabidiol, Multiple sclerosis, Inflammation, VCAM-1, Chemokines, Theiler’s murine encephalomyelitis virus, Infiltrates, Microglia, Adenosine
MS is a chronic, inflammatory demyelinating disease of the CNS that is characterized pathologically by the presence of focal areas ofinflammatory-mediated demyelination in the white matter of thebrain and spinal cord (Trapp and Nave, 2008). The etiology of MS re-mains unknown, although several factors including genetic predispo-sition, viral infection and autoimmunity are thought to be involved.In the early stages of the disease, there is a recruitment of activatedimmune cells that promotes the adhesion and transmigration ofleukocytes across the BBB (Archelos et al., 1999; Lee and Benveniste,1999; Ransohoff, 1999). These events depend on a variety of interactions, including an initial transient contact between circulating leukocytesand the vascular endothelium, mediated by adhesion molecules, andthe binding of leukocytes to chemotactic chemokines present on theendothelial surface. This latter event promotes the expression ofintegrins on the leukocyte surface and ultimately, it leads to diapedesisand leukocyte entry into the CNS (Engelhardt, 2008). It is widely recog-nized that enhanced leukocyte trafficking to the CNS is a key featureof MS (Lassmann, 2008). Therapies have been designed to target CNS inflammation, such as natalizumab (Tysabri®), a humanized antibodyto very late antigen-4 (VLA-4:Krumbholz et al., 2012)thatisessen-tial for the homing of immune cells to the brain and other organs.Indeed, natalizumab is currently prescribed for the treatment of re-lapsing remitting MS (Steinman, 2012). Similarly, cannabis-basedmedicines containing tetrahydrocannabinol (THC) and CBD havealso been approved for the treatment of pain and spasticity in MS(e.g., Sativex®). The promising therapeutic potential of cannabinoids(reviewed byPertwee, 2012) is limited due to the central CB1receptor-mediated psychotropic effects. CBD is the majorCannabisde-rived non-CB1/CB2 ligand that is devoid of psychotropic effects andeven, inhibits many central effects of THC (Zuardi, 2008). Evidenceshows that CBD acts as an immunomodulator (Mechoulam et al.,2007) and exhibits a wide range of anti-inflammatory properties including the inhibition of IL-6 and the activation of antiinflammatorypathways in microglial cells (Kozela et al., 2010). CBD has been shownto induce apoptosis of microglial cells through lipid raft involvement(Wu et al., 2012). Moreover, CBD ameliorates experimental auto-immune encephalomyelitis (EAE) symptomatology by diminishinginflammation, microglial activity and leukocyte infiltrates in the spi-nal cord (Kozela et al., 2011).CBD has a broad spectrum of pharmacological actions (Izzo et al.,2009 ) including the inhibition of an equilibrative nucleoside transporterwhich in turn led to the increase of extracellular adenosine (Carrier et al.,2006 ). In acute injury models CBD diminishes inflammation throughadenosine A2receptors (Ribeiro et al., 2012). Neuroprotective effectsof CBD in hypoxic–ischemic brain damage also involve adenosine A2re-ceptors (Castillo et al., 2010).We previously reported that enhanced endocannabinoid tone andtreatment with synthetic cannabinoid agonists improve motor be-havior in TMEV-IDD mice, reducing infiltration into the spinal cord(Arevalo-Martin et al., 2003; Correa et al., 2005; Docagne et al., 2007;Ortega-Gutierrez et al., 2005). However, the effects of CBD in the induc-tion phase of TMEV-IDD have not been previously described. In thepresent study, we investigated the effects of CBD in the initial stagesof the inflammatory response in the TMEV-IDD experimental model ofMS, and the impact of this treatment on the symptomatology and theneuroinflammation that characterizes the chronic phase of the disease.Finally, we investigated the contribution of adenosine A2Areceptors tothese effects of CBD.