Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
The Synthetic Cannabinoid Ajulemic Acid Targets Scleroderma Fibrosis.
Distler1, Jorg W. H., Galeazzi3, Mauro, Palumbo1, Kathrin, Lorenzini3, Sauro, Akhmetshina1, Alfiya, Epifania3, Balistreri, Selvi2, Enrico
Departement of Internal Medicine III and Institute for Clinical Immunology -Friedrich-Alexander University-Erlangen-Germany
Rheumatology Unit - Departement of Clinical Medicine and Immunological Sciences-University of Siena, Siena, Italy
Rheumatology Unit - Departement of Clinical Medicine and Immunological Sciences-University of Siena- Italy
Substantial evidence supports the involvement of the endocannabinoid system in pathologic fibrosis and the capability of cannabinoids to modify fibrogenesis in scleroderma. Ajulemic acid (AjA) is a non-psychoactive, synthetic analog of tetrahydocannabinol (THC), the main psychoactive ingredient of Cannabis-sativa. AjA binds the peroxisome proliferator-activated receptor-g(PPAR-g), and PPAR-g receptor activation modulates fibrogenesis. Therefore, we performed experiments to determine whether AjA can modify fibrogenesis in scleroderma.
Material and Methods:
skin fibroblasts from scleroderma patients were cultured and treated with increasing concentrations of AjA (0.1, 1, 5 and 10 mM) in the presence or absence of the PPAR-g irreversible antagonist GW9662 (1 and 10 mM) in order to evaluate procollagen production. Cell viability was evaluated using MTT assay and trypan-blue exclusion test. To evaluate AjA effect in vivo, three groups of DBA/2J mice (n=7 in each group) were studied. Group I and II received bleomycin subcutaneously (100 ml/ every other day) for 21 days. In addition to bleomycin, group II was treated orally with AjA (1 mg/kg) for 21 days. Group III only received subcutaneously 100 ml/day of NaCl 0.9%. At day 21 animals were sacrificed. Skin fibrosis was histologically evaluated by quantification of skin thickness and hydroxyproline content. As a marker of fibroblast activation,a-smooth muscle actin (a-SMA) was examined.
AjA as well as the selective PPAR-g antagonist GW9662 did not show any significant toxicity at the concentrations used. Addition of AjA to scleroderma fibroblasts significantly reduced supernatant procollagen concentrations in a dose-dependent manner. This effect was completely reversed by the PPAR-g antagonist GW9662 (10 mM).
AjA treatment (1mg/kg/day for 21days) reduced markedly the dermal fibrosis induced by bleomycin in the animal model. Dermal thickness and hydroxyproline content appeared similar to the untreated control group. AjA treatment also reduced substantially the number of a-SMA positive cells in lesional skin.
we have demonstrated that AjA reduces fibrogenesis, at least in part, through a PPAR-g mediated mechanism. These results and the demonstrated safety of AjA, suggest AjA as an interesting molecule targeting fibrosis in patients with scleroderma.
To cite this abstract, please use the following information:
Distler, Jorg W. H., Galeazzi, Mauro, Palumbo, Kathrin, Lorenzini, Sauro, Akhmetshina, Alfiya, Epifania, Balistreri, et al; The Synthetic Cannabinoid Ajulemic Acid Targets Scleroderma Fibrosis. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :615