title: A novel synthetic cannabinoid derivative inhibits inflammatory liver damage via negative cytokine regulation.
abstract: 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.
authors.affiliation: Pharmos LTD, Kiryat Weizmann, Bld #13b, Rehovot 76326, Israel. lavoni@netvision.net.il
authors.forename: Iris
authors.initials: I
authors.lastname: Lavon
authors.forename: Tatiana
authors.initials: T
authors.lastname: Sheinin
authors.forename: Sigal
authors.initials: S
authors.lastname: Meilin
authors.forename: Efrat
authors.initials: E
authors.lastname: Biton
authors.forename: Ayelet
authors.initials: A
authors.lastname: Weksler
authors.forename: Gilat
authors.initials: G
authors.lastname: Efroni
authors.forename: Avi
authors.initials: A
authors.lastname: Bar-Joseph
authors.forename: George
authors.initials: G
authors.lastname: Fink
authors.forename: Ayelet
authors.initials: A
authors.lastname: Avraham
mesh_terms: D000276:Adjuvants, Immunologic / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002186:Cannabinoids / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use*; D003208:Concanavalin A / Q000633:toxicity; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D005260:Female; D006520:Hepatitis, Animal / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C
chemical_list: D000276:Adjuvants, Immunologic; D002186:Cannabinoids; D016207:Cytokines; D003208:Concanavalin A