Synthetic cannabinoid ajulemic acid exerts potent antifibrotic effects in experimental models of systemic sclerosis

dc.contributor.authorGarcia Gonzalez, Estrella
dc.contributor.authorSelvi, Enrico
dc.contributor.authorBalistreri, Epifania
dc.contributor.authorAkhmetshina, Alfiya
dc.contributor.authorPalumbo, Katrin
dc.contributor.authorLorenzini, Sauro
dc.contributor.authorEnea Lazzerini, Pietro
dc.contributor.authorMontilli, Cinzia
dc.contributor.authorLeopoldo Capecchi, Pier
dc.contributor.authorLucattelli, Monica
dc.contributor.authorBaldi, Caterina
dc.contributor.authorGianchecchi, Elena
dc.contributor.authorGaleazzi, Mauro
dc.contributor.authorLaghi Pasini, Franco
dc.contributor.authorDistler, Jörg H. W.
dc.description.abstractBackground: Cannabinoids modulate fibrogenesis in scleroderma. Ajulemic acid (AjA) is a non-psychoactive synthetic analogue of tetrahydrocannabinol that can bind the peroxisome proliferator-activated receptor-γ (PPAR-γ). Recent evidence suggests a key role for PPAR-γ in fibrogenesis. Objective: To determine whether AjA can modulate fibrogenesis in murine models of scleroderma. Material and methods: Bleomycin-induced experimental fibrosis was used to assess the antifibrotic effects of AjA in vivo. In addition, the efficacy of AjA in pre-established fibrosis was analysed in a modified model of bleomycin-induced dermal fibrosis and in mice overexpressing a constitutively active transforming growth factor β (TGFβ) receptor I. Skin fibrosis was evaluated by quantification of skin thickness and hydroxyproline content. As a marker of fibroblast activation, α-smooth muscle actin was examined. To study the direct effect of AjA in collagen neosynthesis, skin fibroblasts from patients with scleroderma were treated with increasing concentrations of AjA. Protein expression of PPAR-γ, and its endogenous ligand 15d-PGJ2, and TGFβ were assessed before and after AjA treatment. Results: AjA significantly prevented experimental bleomycin-induced dermal fibrosis and modestly reduced its progression when started 3 weeks into the disease. AjA strongly reduced collagen neosynthesis by scleroderma fibroblasts in vitro, an action which was reversed completely by co-treatment with a selective PPAR-γ antagonist. Conclusions: AjA prevents progression of fibrosis in vivo and inhibits fibrogenesis in vitro by stimulating PPAR-γ signalling. Since therapeutic doses of AjA are well tolerated in humans, it is suggested that AjA as an interesting molecule targeting fibrosis in patients with scleroderma.en
dc.format.extent1545 - 1551
dc.identifier.citationAnnals of the Rheumatic Diseases 71.9 (2012): S. 1545-1551. <>
dc.subject.ddcDDC Classification::6 Technik, Medizin, angewandte Wissenschaften :: 61 Medizin und Gesundheit :: 610 Medizin und Gesundheit
dc.titleSynthetic cannabinoid ajulemic acid exerts potent antifibrotic effects in experimental models of systemic sclerosisen
dcterms.publisherFriedrich-Alexander-Universität Erlangen-Nürnberg (FAU)
local.journal.titleAnnals of the Rheumatic Diseases
local.subject.fakultaetMedizinische Fakultät
local.subject.sammlungUniversität Erlangen-Nürnberg / Allianzlizenzen: Alle Beiträge sind mit Zustimmung der Rechteinhaber aufgrund einer DFG-geförderten Allianzlizenz frei zugänglich. / Allianzlizenzen 2012
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