A cannabigerol derivative suppresses immune responses and protects mice from experimental autoimmune encephalomyelitis

PLoS One. 2014 Apr 11;9(4):e94733. doi: 10.1371/journal.pone.0094733. eCollection 2014.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axons / drug effects
  • Axons / immunology
  • Axons / pathology
  • Biomarkers
  • Cannabinoids / administration & dosage
  • Cannabinoids / pharmacology*
  • Cell Line
  • Cytokines / metabolism
  • Encephalomyelitis, Autoimmune, Experimental / drug therapy
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • Encephalomyelitis, Autoimmune, Experimental / metabolism
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Female
  • Humans
  • Immunosuppressive Agents / administration & dosage
  • Immunosuppressive Agents / pharmacology*
  • Inflammation Mediators / metabolism
  • Macrophages / drug effects
  • Macrophages / immunology
  • Macrophages / metabolism
  • Mice
  • Quinones / administration & dosage
  • Quinones / pharmacology
  • T-Lymphocyte Subsets / drug effects
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism

Substances

  • Biomarkers
  • Cannabinoids
  • Cytokines
  • Immunosuppressive Agents
  • Inflammation Mediators
  • Quinones
  • VCE-003
  • cannabigerol

Grant support

This work was supported by the Ministry of the Economy and Competition (MINECO) grants IPT-2011-0861-900000 (EM and CG), SAF2010-19292 (EM), SAF2010-17501 (CG) and by Red Española de Esclerosis Múltiple (REEM) RD12/0032/0008 (CG) sponsored by the Fondo de Investigación Sanitaria (FIS). MINECO IPT-2011-0861-900000, and FEDER-INTERCONNECTA ITC-20111029 grants to VivaCell Biotechnology España supported CN and MLB. VivaCell Biotechnology provided support in the form of salaries for authors (MLB and EM), but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the author contribution's section.