Pharmacological modulation of the endocannabinoid system in a viral model of multiple sclerosis.
ABSTRACT Theiler's virus infection of the central nervous system (CNS) induces an immune-mediated demyelinating disease in susceptible mouse strains and serves as a relevant infection model for human multiple sclerosis (MS). Cannabinoids have been shown to exert beneficial effects on animal models of MS and evidence suggests that the endocannabinoid system plays a role in the tonic control of spasticity. In this study we show that OMDM1 [(R)-N-oleoyl-(1'-hydroxybenzyl)-2'-ethanolamine] and OMDM2 [(S)-N-oleoyl-(1'-hydroxybenzyl)-2'-ethanolamine], two selective inhibitors of the putative endocannabinoid transporter and hence of endocannabinoid inactivation, provide an effective therapy for Theiler murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD). Treatment of TMEV-infected mice with OMDM1 and OMDM2 enhanced anandamide levels in the spinal cord and ameliorated motor symptoms. This was associated with a down-regulation of inflammatory responses in the spinal cord. In addition we show that OMDM1 and OMDM2 down-regulate macrophage function by (i) decreasing the surface expression of major histocompatibility complex (MHC) class II molecules, (ii) inhibiting nitric oxide synthase-2 (NOS-2) expression and (iii) reducing the production of the pro-inflammatory cytokines interleukin-1beta (IL-1beta) and interleukin-12 (IL-12p40). Taken together, these results point to the manipulation of the endocannabinoid system as a possible strategy to develop future MS therapeutic drugs.
Article: El sistema cannabinoide en situaciones de neuroinflamación: perspectivas terapéuticas en la esclerosis múltiple[show abstract] [hide abstract]
ABSTRACT: [EN]Introduction. The endocannabinoid system consists of cannabinoid receptors, endogenous ligands and the enzymatic elements involved in their synthesis and breakdown. Aim. To report on currently held knowledge about the functioning of the system as a modulator of the neuroinflammatory processes associated with chronic diseases such as multiple sclerosis. Development. Cannabinoids are synthesised and released on demand and their production increases in times of neuroinflammation and neural damage. In this context then, their actions in the microglial cells and in the astrocytes are characterised by a lowered expression of inflammatory mediators and pro-inflammatory cytokines. Furthermore, cannabinoids can play a role as neuroprotectors by means of different types of mechanisms and, in experimental models of multiple sclerosis, they slow down the symptoms, reduce inflammation and can favour remyelination. Conclusions. The clinical use of cannabinoids or pharmacological agents that affect the endogenous cannabinoid system during inflammation of the central nervous system and in multiple sclerosis is currently under consideration and subject to debate. Detailed analysis of the results obtained over the past decade has made it possible to establish the existence of several mechanisms of action of cannabinoids in pathologies affecting the central nervous system that are accompanied by chronic inflammation. Likewise, they also clearly show that the cannabinoid system is an interesting proposal as a new therapeutic tool. [ES]Introducción. El sistema endocannabinoide está constituido por los receptores cannabinoides, los ligandos endógenos y los elementos enzimáticos implicados en su síntesis y degradación. Objetivo. Describir el estado actual de conocimiento sobre la función del sistema como modulador de los procesos neuroinflamatorios asociados con enfermedades crónicas como la esclerosis múltiple. Desarrollo. Los cannabinoides se sintetizan y se liberan en demanda y su producción aumenta en situaciones de neuroinflamación y de daño neural. En este contexto, sus acciones en la microglía y en los astrocitos se caracterizan por una disminución en la expresión de mediadores inflamatorios y de citocinas proinflamatorias. Además, los cannabinoides pueden ejercer acciones neuroprotectoras a través de diferentes tipos de mecanismos y en modelos experimentales de esclerosis múltiple atenúan la sintomatología, disminuyen la inflamación y pueden favorecer la remielinización. Conclusiones. El uso clínico de cannabinoides o agentes farmacológicos que inciden en el sistema endógeno cannabinoide durante la inflamación del sistema nervioso central y en la esclerosis múltiple está actualmente sometido a consideración y debate. El análisis detallado de los resultados obtenidos en la última década ha permitido establecer que son múltiples los mecanismos de actuación de los cannabinoides en patologías del sistema nervioso central que cursan con inflamación crónica y ponen de manifiesto el interés del sistema cannabinoide como nueva herramienta terapéutica. Grupo de Neuroinmunología. Instituto Cajal. Centro Superior de Investigaciones Científicas. Madrid. b Grupo de Neuroinflamación. Hospital Nacional de Parapléjicos. Toledo. c Departamento de Química Orgánica. Facultad de Ciencias Químicas. Universidad Complutense de Madrid. Madrid, España. Peer reviewed
Article: Cannabinoids and Viral Infections.[show abstract] [hide abstract]
ABSTRACT: Exogenous cannabinoids or receptor antagonists may influence many cellular and systemic host responses. The anti-inflammatory activity of cannabinoids may compromise host inflammatory responses to acute viral infections, but may be beneficial in persistent infections. In neurons, where innate antiviral/pro-resolution responses include the activation of NOS-1, inhibition of Ca(2+) activity by cannabinoids, increased viral replication and disease. This review examines the effect(s) of cannabinoids and their antagonists in viral infections.Pharmaceuticals 06/2010; 3(6):1873-1886.
Article: 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.[show abstract] [hide abstract]
ABSTRACT: 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. 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. 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. 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.Journal of Neuroinflammation 08/2011; 8:102. · 3.83 Impact Factor