Publication: VCE-004.3, a cannabidiol aminoquinone derivative, prevents bleomycin-induced skin fibrosis and inflammation through PPARγ- and CB2 receptor-dependent pathways.
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Identifiers
Date
2018-07-12
Authors
Del Rio, Carmen
Cantarero, Irene
Palomares, Belen
Gomez-Cañas, Maria
Fernandez-Ruiz, Javier
Pavicic, Carolina
Garcia-Martin, Adela
Luz Bellido, Maria
Ortega-Castro, Rafaela
Perez-Sanchez, Carlos
Advisors
Journal Title
Journal ISSN
Volume Title
Publisher
John Wiley & Sons
Abstract
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. 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. 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. 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.
Description
MeSH Terms
Animals
Bleomycin
Cannabidiol
Cell Differentiation
Cell Movement
Cells, Cultured
Dose-Response Relationship, Drug
Female
Fibrosis
Humans
Inflammation
Mice
Mice, Inbred BALB C
Molecular Docking Simulation
Molecular Structure
Bleomycin
Cannabidiol
Cell Differentiation
Cell Movement
Cells, Cultured
Dose-Response Relationship, Drug
Female
Fibrosis
Humans
Inflammation
Mice
Mice, Inbred BALB C
Molecular Docking Simulation
Molecular Structure
DeCS Terms
Bleomicina
Células cultivadas
Diferenciación celular
Estructura molecular
Inflamación
Movimiento celular
Ratones
Simulación del acoplamiento molecular
Células cultivadas
Diferenciación celular
Estructura molecular
Inflamación
Movimiento celular
Ratones
Simulación del acoplamiento molecular
CIE Terms
Keywords
NIH 3T3 Cells, PPAR gamma, Quinones, Receptor, Cannabinoid, CB1, Receptor, Cannabinoid, CB2, Skin, Structure-Activity Relationship
Citation
Del Rio C, Cantarero I, Palomares B, Gómez-Cañas M, Fernández-Ruiz J, Pavicic C, et al. VCE-004.3, a cannabidiol aminoquinone derivative, prevents bleomycin-induced skin fibrosis and inflammation through PPARγ- and CB2 receptor-dependent pathways. Br J Pharmacol. 2018 Oct;175(19):3813-3831