A novel synthetic cannabinoid derivative inhibits inflammatory liver damage via negative cytokine regulation

Mol Pharmacol. 2003 Dec;64(6):1334-41. doi: 10.1124/mol.64.6.1334.


The therapeutic potential of cannabinoids has been described previously for several inflammatory diseases, but the molecular mechanisms underlying the anti-inflammatory properties of cannabinoids are not well understood. In this study, we investigated the mechanism of action of a novel synthetic cannabinoid, [(+)(6aS,10aS)-6,6-Dimethyl-3-(1,1-dimethylheptyl)-1-hydroxy-9-(1H-imidazol-2-ylsulfanylmethyl]-6a,7,10,10a-tetrahydro-6H-dibenzo[b,d]pyran (PRS-211,092) that has no psychotropic effects but exhibits immunomodulatory properties. Treatment with PRS-211,092 significantly decreased Concanavalin A-induced liver injury in mice that was accompanied by: 1) promotion of early gene expression of interleukin (IL)-6 and IL-10 that play a protective role in this model; 2) induction of early gene expression of the suppressors of cytokine signaling (SOCS-1 and 3), followed by 3) inhibition of several pro-inflammatory mediators, including IL-2, monocyte chemoattractant protein-1 (MCP-1), IL-1beta, interferon-gamma, and tumor necrosis factor alpha. Based on these results, we propose a mechanism by which PRS-211,092 stimulates the expression of IL-6, IL-10 and the SOCS proteins that, in turn, negatively regulates the expression of pro-inflammatory cytokines. Negative regulation by PRS-211,092 was further demonstrated in cultured T cells, where it inhibited IL-2 production and nuclear factor of activated T cells activity. These findings suggest that this cannabinoid derivative is an immunomodulator that could be developed as a potential drug for hepatitis as well as for other short- or long-term inflammatory diseases.

MeSH terms

  • Adjuvants, Immunologic / chemical synthesis
  • Adjuvants, Immunologic / pharmacology
  • Adjuvants, Immunologic / therapeutic use
  • Animals
  • Cannabinoids / chemical synthesis*
  • Cannabinoids / pharmacology
  • Cannabinoids / therapeutic use*
  • Concanavalin A / toxicity
  • Cytokines / antagonists & inhibitors*
  • Cytokines / metabolism*
  • Female
  • Hepatitis, Animal / metabolism
  • Hepatitis, Animal / pathology
  • Hepatitis, Animal / prevention & control*
  • Mice
  • Mice, Inbred BALB C


  • Adjuvants, Immunologic
  • Cannabinoids
  • Cytokines
  • Concanavalin A