%0 Journal Article
%A Río, Carmen del
%A Gómez Cañas, María
%A Fernández Ruiz, José Javier
%A Muñoz, Eduardo
%T VCE-004.3, a cannabidiol aminoquinone derivative, prevents bleomycin-induced skin fibrosis and inflammation through PPARγ- and CB2 receptor-dependent pathways
%D 2018
%@ 0007-1188
%@ 1476-5381
%U https://hdl.handle.net/20.500.14352/93336
%X BACKGROUND AND PURPOSEThe endocannabinoid system and PPARγ are important targets for the development of novel compounds against fibrotic diseasessuch as systemic sclerosis (SSc), also called scleroderma. The aim of this study was to characterize VCE-004.3, a novel cannabidiolderivative, and study its anti-inflammatory and anti-fibrotic activities.EXPERIMENTAL APPROACHThe binding of VCE-004.3 to CB1 and CB2 receptors and PPARγ and its effect on their functional activities were studied in vitro andin silico. Anti-fibrotic effects of VCE-004.3 were investigated in NIH-3T3 fibroblasts and human dermal fibroblasts. To assess itsanti-inflammatory and anti-fibrotic efficacy in vivo, we used two complementary models of bleomycin-induced fibrosis. Its effecton ERK1/2 phosphorylation induced by IgG from SSc patients and PDGF was also investigated.KEY RESULTSVCE-004.3 bound to and activated PPARγ and CB2 receptors and antagonized CB1 receptors. VCE-004.3 bound to an alternativesite at the PPARγ ligand binding pocket. VCE-004.3 inhibited collagen gene transcription and synthesis and prevented TGFβ induced fibroblast migration and differentiation to myofibroblasts. It prevented skin fibrosis, myofibroblast differentiation andERK1/2 phosphorylation in bleomycin-induced skin fibrosis. Furthermore, it reduced mast cell degranulation, macrophage acti vation, T-lymphocyte infiltration, and the expression of inflammatory and profibrotic factors. Topical application of VCE-004.3also alleviated skin fibrosis. Finally, VCE-004.3 inhibited PDGF-BB- and SSc IgG-induced ERK1/2 activation in fibroblasts.CONCLUSIONS AND IMPLICATIONSVCE-004.3 is a novel semisynthetic cannabidiol derivative that behaves as a dual PPARγ/CB2 agonist and CB1 receptor modulatorthat could be considered for the development of novel therapies against different forms of scleroderma.
%~