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Sci Rep. 2016 Feb 18;6:21703. doi: 10.1038/srep21703.

The cannabinoid quinol VCE-004.8 alleviates bleomycin-induced scleroderma and exerts potent antifibrotic effects through peroxisome proliferator-activated receptor-γ and CB2 pathways.

Author information

1
Maimonides Biomedical Research Institute of Córdoba, Reina Sofía University Hospital, Dept of Cell Biology, Physiology and Immunology, University of Córdoba, Avda Menéndez Pidal s/n, 14004. Córdoba, Spain.
2
VivaCell Biotechnology España, Parque Científico Tecnológico Rabanales 21, 14014, Córdoba, Spain.
3
Instituto Universitario de Investigación en Neuroquímica, Departamento de Bioquímica y Biología Molecular III, Facultad de Medicina, Universidad Complutense, Madrid, Spain.
4
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
5
Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.
6
Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche, Via Bovio 6, 28100, Novara, Italy.

Abstract

Scleroderma is a group of rare diseases associated with early and transient inflammation and vascular injury, followed by fibrosis affecting the skin and multiple internal organs. Fibroblast activation is the hallmark of scleroderma, and disrupting the intracellular TGFβ signaling may provide a novel approach to controlling fibrosis. Because of its potential role in modulating inflammatory and fibrotic responses, both PPARγ and CB2 receptors represent attractive targets for the development of cannabinoid-based therapies. We have developed a non-thiophilic and chemically stable derivative of the CBD quinol (VCE-004.8) that behaves as a dual agonist of PPARγ and CB2 receptors, VCE-004.8 inhibited TGFβ-induced Col1A2 gene transcription and collagen synthesis. Moreover, VCE-004.8 inhibited TGFβ-mediated myofibroblast differentiation and impaired wound-healing activity. The anti-fibrotic efficacy in vivo was investigated in a murine model of dermal fibrosis induced by bleomycin. VCE-004.8 reduced dermal thickness, blood vessels collagen accumulation and prevented mast cell degranulation and macrophage infiltration in the skin. These effects were impaired by the PPARγ antagonist T0070907 and the CB2 antagonist AM630. In addition, VCE-004.8 downregulated the expression of several key genes associated with fibrosis, qualifying this semi-synthetic cannabinoid as a novel compound for the management of scleroderma and, potentially, other fibrotic diseases.

PMID:
26887982
PMCID:
PMC4757881
DOI:
10.1038/srep21703
[Indexed for MEDLINE]
Free PMC Article

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