Article

Pharmacological modulation of the endocannabinoid system in a viral model of multiple sclerosis.

Neuroimmunology Group, Neural Plasticity Department, Cajal Institute, CSIC, 28002 Madrid, Spain.
Journal of Neurochemistry (impact factor: 4.06). 04/2005; 92(6):1327-39. DOI:10.1111/j.1471-4159.2004.02979.x pp.1327-39
Source: PubMed

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.

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    Article: El sistema cannabinoide en situaciones de neuroinflamación: perspectivas terapéuticas en la esclerosis múltiple
    F Docagne, L Mestre, F Correa, D. Clemente, S Ortega-Guiterrez, E. Molina, A. Arévalo-Martín, José Borrell, Carmen Guaza
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    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
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    Article: Cannabinoids and Viral Infections.
    Carol Shoshkes Reiss
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    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.
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    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.
    Leyre Mestre, Paula M Iñigo, Miriam Mecha, Fernando G Correa, Miriam Hernangómez-Herrero, Frida Loría, Fabian Docagne, José Borrell, Carmen Guaza
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    Journal of Neuroinflammation 08/2011; 8:102. · 3.83 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.

Keywords

ameliorated motor symptoms
 
anandamide levels
 
central nervous system
 
endocannabinoid inactivation
 
endocannabinoid system
 
future MS therapeutic drugs
 
human multiple sclerosis
 
IL-1beta
 
immune-mediated demyelinating disease
 
inflammatory responses
 
OMDM2 [(S)-N-oleoyl-(1'-hydroxybenzyl)-2'-ethanolamine]
 
pro-inflammatory cytokines interleukin-1beta
 
putative endocannabinoid transporter
 
relevant infection model
 
selective inhibitors
 
surface expression
 
susceptible mouse strains
 
Theiler murine encephalomyelitis virus-induced demyelinating disease
 
Theiler's virus infection
 
tonic control