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SAT0032 The synthetic cannabinoid ajulemic acid exerts potent anti-fibrotic effects in experimental models of systemic sclerosis
  1. E. Garcia-Gonzalez1,
  2. E. Selvi1,
  3. E. Balistreri1,
  4. A. Akhmetshina2,
  5. K. Palumbo2,
  6. S. Lorenzini1,
  7. C. Montilli1,
  8. C. Baldi1,
  9. M. Galeazzi1,
  10. J.H. Distler2
  1. 1Clinical Medicine and Immunological Sciences, University of Siena, Siena, Italy
  2. 2Immunology and Rheumatology, University of Erlangen, Erlangen, Germany

Abstract

Background Cannabinoids are able to modulate fibrogenesis in scleroderma. Ajulemic acid (AjA) is a non-psychoactive synthetic analogue of tetrahydrocannabinol (THC), able to bind the peroxisome proliferator-activated receptor-γ (PPAR-γ) (1). Recent evidence suggests a key role for PPAR-γ in fibrogenesis (2).

Objectives We aimed to determine whether AjA can modulate fibrogenesis in murine models of scleroderma.

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 analyzed in a modified model of bleomycin-induced dermal fibrosis and in mice overexpressing a constitutively active transforming growth factor-β (TGF-β) receptor I (AdTGFbRI mice). Skin fibrosis was evaluated by quantification of skin thickness and hydroxyproline content. As a marker of fibroblast activation, α-smooth muscle actin (α-SMA) was examined.

Results In acute model of experimental dermal fibrosis oral administration of AjA (1mg/kg/day) prevented development of skin fibrosis, and reduced skin thickness nearly to control levels. Consistently production of collagen, determined by quantification of dermal hydroxyproline content, was reduced substantially in mice treated with AjA. Treatment significantly reduced the number of myofibroblasts in lesional skin up to 26±5% (p<0.05). After eight weeks AdTGFbRI mice showed twofold increase in dermal thickness compared with Ad-Lac-z control mice (p<0.05). Oral administration of AjA (1mg/kg/day) for eight weeks reduced development of skin thickness up to 30±6% (mean±SD) compared to AdTGFbRI mice (p<0.05). AjA treatment (1mg/kg/day) induced a mean reduction of 30±13% (mean±SD) in hydroxyproline content (p<0.05). AjA treatment significantly reduced the number of myofibroblasts in lesional skin up to 26±3% (p<0.001). AjA effect in pre-established fibrosis, analyzed in a modified model of bleomycin-induced dermal fibrosis in the last 3 weeks, reduced collagen deposition by 10±8% (mean±SD) (p<0.05). Thus, AjA administration for the last 3 weeks of bleomycin challenge stopped further progression of fibrosis, but did not alter pre-existing ECM accumulation and dermal thickness.The number of myofibroblasts after AjA treatment was significantly reduced in lesional skin up to 25±16% (mean±SD) compared to bleomycin challenged mice (p<0.05).

Conclusions We demonstrate that AjA prevents progression of fibrosis in-vivo and that inhibits fibrogenesis in-vitro by stimulating PPAR-γ signaling. Since therapeutic doses of AjA are well tolerated in humans, we suggest AjA as an interesting molecule targeting fibrosis in patients with scleroderma.

  1. Burstein S. Ajulemic acid (IP-751): synthesis, proof of principle, toxicity studies, and clinical trials. AAPS J. 2005;7:143-8.

  2. Wei J, Ghosh AK, Sargent JL et al. PPARγ downregulation by TGFβ in fibroblast and impaired expression and function in systemic sclerosis: a novel mechanism for progressive fibrogenesis. PLoS One. 2010;5:e13778

Disclosure of Interest None Declared

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