title: A cannabigerol derivative suppresses immune responses and protects mice from experimental autoimmune encephalomyelitis.
abstract: Phytocannabinoids that do not produce psychotropic effects are considered of special interest as novel therapeutic agents in CNS diseases. A cannabigerol quinone, the compound VCE-003, has been shown to alleviate symptoms in a viral model of multiple sclerosis (MS). Hence, we studied T cells and macrophages as targets for VCE-003 and its efficacy in an autoimmune model of MS. Proliferation, cell cycle, expression of activation markers was assessed by FACs in human primary T cells, and cytokine and chemokine production was evaluated. Transcription was studied in Jurkat cells and RAW264.7 cells were used to study the effects of VCE-003 on IL-17-induced macrophage polarization to a M1 phenotype. Experimental autoimmune encephalomyelitis (EAE) was induced by myelin oligodendrocyte glycoprotein (MOG₃₅₋₅₅) immunization and spinal cord pathology was assessed by immunohistochemistry. Neurological impairment was evaluated using disease scores. We show here that VCE-003 inhibits CD3/CD28-induced proliferation, cell cycle progression and the expression of the IL-2Rα and ICAM-1 activation markers in human primary T cells. VCE-003 inhibits the secretion of Th1/Th17 cytokines and chemokines in primary murine T cells, and it reduces the transcriptional activity of the IL-2, IL-17 and TNFα promoters induced by CD3/CD28. In addition, VCE-003 and JWH-133, a selective CB2 agonist, dampened the IL-17-induced polarization of macrophages to a pro-inflammatory M1 profile. VCE-003 also prevented LPS-induced iNOS expression in microglia. VCE-003 ameliorates the neurological defects and the severity of MOG-induced EAE in mice through CB2 and PPARγ receptor activation. A reduction in cell infiltrates, mainly CD4+ T cells, was observed, and Th1 and Th17 responses were inhibited in the spinal cord of VCE-003-treated mice, accompanied by weaker microglial activation, structural preservation of myelin sheets and reduced axonal damage. This study highlights the therapeutic potential of VCE-003 as an agent for the treatment of human immune diseases with both inflammatory and autoimmune components.
authors.affiliation: Neuroimmunology Group, Functional and System Neurobiology Department, Instituto Cajal, Madrid, Spain.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Carrillo-Salinas
authors.affiliation: VivaCell Biotechnology España, Parque Científico Tecnológico de Córdoba, Córdoba, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Navarrete
authors.affiliation: Neuroimmunology Group, Functional and System Neurobiology Department, Instituto Cajal, Madrid, Spain.
authors.forename: Miriam
authors.initials: M
authors.lastname: Mecha
authors.affiliation: Neuroimmunology Group, Functional and System Neurobiology Department, Instituto Cajal, Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Feliú
authors.affiliation: Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía, Universidad de Córdoba, Córdoba, Spain.
authors.forename: Juan A
authors.initials: JA
authors.lastname: Collado
authors.affiliation: Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía, Universidad de Córdoba, Córdoba, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Cantarero
authors.affiliation: VivaCell Biotechnology España, Parque Científico Tecnológico de Córdoba, Córdoba, Spain.
authors.forename: María L
authors.initials: ML
authors.lastname: Bellido
authors.affiliation: Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía, Universidad de Córdoba, Córdoba, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Muñoz
authors.affiliation: Neuroimmunology Group, Functional and System Neurobiology Department, Instituto Cajal, Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Guaza
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D015415:Biomarkers; D002186:Cannabinoids / Q000008:administration & dosage / Q000494:pharmacology*; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D011809:Quinones / Q000008:administration & dosage / Q000494:pharmacology; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
chemical_list: D015415:Biomarkers; D002186:Cannabinoids; D016207:Cytokines; D007166:Immunosuppressive Agents; D018836:Inflammation Mediators; D011809:Quinones; C581223:VCE-003; C037036:cannabigerol
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