RT Journal Article
T1 VCE-004.3, a cannabidiol aminoquinone derivative, prevents bleomycin-induced skin fibrosis and inflammation through PPARγ- and CB2 receptor-dependent pathways.
A1 Del Rio, Carmen
A1 Cantarero, Irene
A1 Palomares, Belen
A1 Gomez-Cañas, Maria
A1 Fernandez-Ruiz, Javier
A1 Pavicic, Carolina
A1 Garcia-Martin, Adela
A1 Luz Bellido, Maria
A1 Ortega-Castro, Rafaela
A1 Perez-Sanchez, Carlos
A1 Lopez-Pedrera, Chary
A1 Appendino, Giovanni
A1 Calzado, Marco A
A1 Muñoz, Eduardo
K1 NIH 3T3 Cells
K1 PPAR gamma
K1 Quinones
K1 Receptor, Cannabinoid, CB1
K1 Receptor, Cannabinoid, CB2
K1 Skin
K1 Structure-Activity Relationship
AB 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.
PB John Wiley & Sons
YR 2018
FD 2018-07-12
LK http://hdl.handle.net/10668/12741
UL http://hdl.handle.net/10668/12741
LA en
NO 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
NO This work was partially supported by the MINECO grantRTC-2015-3364 cofounded by the European DevelopmentRegional Fund in the Framework of the Operative Pro-gram ‘Reinforcement of research, technological develop-ment and innovation’. E.M. was also supported by theMINECO grant SAF2014-53763-P. B.P. is a predoctoral fel-low supported by the i-PFIS program, Instituto de SaludCarlos III (IFI15/00022; European Social Fund “investingin your future”)
DS RISalud
RD Apr 17, 2025