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