Abstract
BACKGROUND AND PURPOSE:
The endocannabinoid system (ECS) as well as PPARγ are relevant 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 to study it anti-inflammatory and anti-fibrotic activities.
EXPERIMENTAL APPROACH:
CB1 , CB2 and PPARγbinding and functional activities were studied in vitro and in silico. The anti-fibrotic effects of VCE-004.3 were investigated in NIH-3T3 fibroblasts and in human dermal fibroblasts. To assess the anti-inflammatory and anti-fibrotic efficacy of VCE-004.3 in vivo we used two complementary models of bleomycin-induced fibrosis. The effect of VCE-004.3 on ERK1/2 phosphorylation induced by IgG from SSc patients and PDGF was also investigated.
KEY RESULTS:
VCE-004.3 binds and activates PPARγ and CB2 receptors and antagonizes CB1 receptor. VCE-004.3 binds to an alternative site at the PPARγ ligand-binding pocket (LBP). VCE-004.3 inhibits collagen gene transcription and synthesis and prevents TGFβ-induced fibroblast migration and differentiation to myofibroblasts. VCE-004.3 prevents skin fibrosis, myofibroblast differentiation and ERK1/2 phosphorylation in bleomycin-induced skin fibrosis. In addition, VCE-004.3 reduces mast cell degranulation, macrophage activation, T lymphocytes infiltration, and the expression of inflammatory and profibrotic factors. Topical application of VCE-004.3 also alleviates skin fibrosis. Finally, VCE-004.3 inhibits PDGF-BB- and SSc IgG-induced ERK1/2 activation in fibroblasts.
CONCLUSION AND IMPLICATIONS:
VCE-004.3 is a novel semi-synthetic cannabidiol derivative behaving 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.
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- PMID: 30033591
- DOI: 10.1111/bph.14450
