VCE-004.3, a cannabidiol aminoquinone derivative, prevents bleomycin-induced skin fibrosis and inflammation through PPARγ- and CB2 receptor-dependent pathways.

Autor:	del Rio, Carmen, Cantarero, Irene, Palomares, Belén, Gómez‐Cañas, María, Fernández‐Ruiz, Javier, Pavicic, Carolina, García‐Martín, Adela, Luz Bellido, Maria, Ortega‐Castro, Rafaela, Pérez‐Sánchez, Carlos, López‐Pedrera, Chary, Appendino, Giovanni, Calzado, Marco A., Muñoz, Eduardo, Gómez-Cañas, María, Fernández-Ruiz, Javier, García-Martín, Adela, Ortega-Castro, Rafaela, Pérez-Sánchez, Carlos, López-Pedrera, Chary
Předmět:	CANNABINOIDS BLEOMYCIN FIBROSIS SCLERODERMA (Disease) PEROXISOME proliferator-activated receptors CANNABINOID receptors EXTRACELLULAR signal-regulated kinases FIBROBLASTS PROTEIN metabolism ANIMAL experimentation BIOCHEMISTRY CELL culture CELL differentiation CELL receptors CELLS CELL motility COMPUTER simulation DOSE-effect relationship in pharmacology HYDROCARBONS INFLAMMATION PHENOMENOLOGY MICE MOLECULAR structure PROTEINS QUINONE RESEARCH funding SKIN
Zdroj:	British Journal of Pharmacology; Oct2018, Vol. 175 Issue 19, p3813-3831, 19p, 8 Color Photographs, 1 Black and White Photograph, 1 Chart, 3 Graphs
Abstrakt:	Background and Purpose: The endocannabinoid system and PPARγ are important targets for the development of novel compounds against fibrotic diseases such as systemic sclerosis (SSc), also called scleroderma. The aim of this study was to characterize VCE-004.3, a novel cannabidiol derivative, and study its anti-inflammatory and anti-fibrotic activities.Experimental Approach: The binding of VCE-004.3 to CB1 and CB2 receptors and PPARγ and its effect on their functional activities were studied in vitro and in silico. Anti-fibrotic effects of VCE-004.3 were investigated in NIH-3T3 fibroblasts and human dermal fibroblasts. To assess its anti-inflammatory and anti-fibrotic efficacy in vivo, we used two complementary models of bleomycin-induced fibrosis. Its effect on ERK1/2 phosphorylation induced by IgG from SSc patients and PDGF was also investigated.Key Results: VCE-004.3 bound to and activated PPARγ and CB2 receptors and antagonized CB1 receptors. VCE-004.3 bound to an alternative site 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 and ERK1/2 phosphorylation in bleomycin-induced skin fibrosis. Furthermore, it reduced mast cell degranulation, macrophage activation, T-lymphocyte infiltration, and the expression of inflammatory and profibrotic factors. Topical application of VCE-004.3 also alleviated skin fibrosis. Finally, VCE-004.3 inhibited PDGF-BB- and SSc IgG-induced ERK1/2 activation in fibroblasts.Conclusions and Implications: VCE-004.3 is a novel semisynthetic cannabidiol derivative that behaves as a dual PPARγ/CB2 agonist and CB1 receptor modulator that could be considered for the development of novel therapies against different forms of scleroderma. [ABSTRACT FROM AUTHOR]
Databáze:	Complementary Index
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