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VCE-004.3, a cannabidiol aminoquinone derivative, prevents bleomycin-induced skin fibrosis and inflammation through PPARγ- and CB2 receptor-dependent pathways.
- Source :
- British Journal of Pharmacology; Oct2018, Vol. 175 Issue 19, p3813-3831, 19p, 8 Color Photographs, 1 Black and White Photograph, 1 Chart, 3 Graphs
- Publication Year :
- 2018
-
Abstract
- <bold>Background and Purpose: </bold>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.<bold>Experimental Approach: </bold>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.<bold>Key Results: </bold>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.<bold>Conclusions and Implications: </bold>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]
- Subjects :
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 00071188
- Volume :
- 175
- Issue :
- 19
- Database :
- Complementary Index
- Journal :
- British Journal of Pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 131754726
- Full Text :
- https://doi.org/10.1111/bph.14450