2026-06-27T23:03:59Zhttps://docta.ucm.es/rest/oai/requestoai:docta.ucm.es:20.500.14352/933362024-01-17T02:38:37Zcom_20.500.14352_14col_20.500.14352_15
Docta Complutense
author
Río, Carmen del
author
Gómez Cañas, María
author
Fernández Ruiz, José Javier
author
Muñoz, Eduardo
2024-01-16T11:47:59Z
2024-01-16T11:47:59Z
2018-08-23
Del Rio C, Cantarero I, Palomares B, Gómez-Cañas M, Fernández-Ruiz J, Pavicic C, García-Martín A, Luz Bellido M, Ortega-Castro R, Pérez-Sánchez C, López-Pedrera C, Appendino G, Calzado MA, Muñoz E. 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, 175(19):3813-3831.
0007-11881476-5381
10.1111/bph.14450
https://hdl.handle.net/20.500.14352/93336
https://bpspubs.onlinelibrary.wiley.com/journal/14765381
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 acti vation, 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.
eng
Attribution-NonCommercial-NoDerivatives 4.0 International
VCE-004.3, a cannabidiol aminoquinone derivative, prevents bleomycin-induced skin fibrosis and inflammation through PPARγ- and CB2 receptor-dependent pathways
journal article
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Publicación 21. Del Río et al 2018.pdf