title: The cannabinoid quinol VCE-004.8 alleviates bleomycin-induced scleroderma and exerts potent antifibrotic effects through peroxisome proliferator-activated receptor-γ and CB2 pathways.
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.
authors.affiliation: 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.
authors.forename: Carmen
authors.initials: C
authors.lastname: del Río
authors.affiliation: VivaCell Biotechnology España, Parque Científico Tecnológico Rabanales 21, 14014, Córdoba, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Navarrete
authors.affiliation: VivaCell Biotechnology España, Parque Científico Tecnológico Rabanales 21, 14014, Córdoba, Spain.
authors.forename: Juan A
authors.initials: JA
authors.lastname: Collado
authors.affiliation: VivaCell Biotechnology España, Parque Científico Tecnológico Rabanales 21, 14014, Córdoba, Spain.
authors.forename: M Luz
authors.initials: ML
authors.lastname: Bellido
authors.affiliation: Instituto Universitario de Investigación en Neuroquímica, Departamento de Bioquímica y Biología Molecular III, Facultad de Medicina, Universidad Complutense, Madrid, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.|Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Gómez-Cañas
authors.affiliation: Instituto Universitario de Investigación en Neuroquímica, Departamento de Bioquímica y Biología Molecular III, Facultad de Medicina, Universidad Complutense, Madrid, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.|Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.
authors.forename: M Ruth
authors.initials: MR
authors.lastname: Pazos
authors.affiliation: Instituto Universitario de Investigación en Neuroquímica, Departamento de Bioquímica y Biología Molecular III, Facultad de Medicina, Universidad Complutense, Madrid, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.|Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Fernández-Ruiz
authors.affiliation: Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche, Via Bovio 6, 28100, Novara, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Pollastro
authors.affiliation: Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche, Via Bovio 6, 28100, Novara, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Appendino
authors.affiliation: 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.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Calzado
authors.affiliation: 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.
authors.forename: Irene
authors.initials: I
authors.lastname: Cantarero
authors.affiliation: 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.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Muñoz
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000009:adverse effects*; D002186:Cannabinoids / Q000008:administration & dosage* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D006873:Hydroquinones / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D041681:NIH 3T3 Cells; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism*; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000378:metabolism*; D012594:Scleroderma, Localized / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D002186:Cannabinoids; D006873:Hydroquinones; D047495:PPAR gamma; D043885:Receptor, Cannabinoid, CB2; D001761:Bleomycin