tropisetron and Scleroderma--Systemic

There is increasing evidence that serotonin (5-hydroxytryptamine [5-HT]) and distinct 5-HT receptors are involved in the pathogenesis of systemic sclerosis. The aim of this study was to test the hypothesis that tropisetron, a routinely used antiemetic agent previously characterized as a 5-HT(3/4) receptor-modulating agent, can directly affect collagen synthesis in vitro and attenuate experimentally induced fibrosis in vivo.. Functional in vitro studies were performed using human dermal fibroblasts (HDFs). Signal transduction studies included immunofluorescence analysis, Western immunoblotting, promoter reporter assays, cAMP/Ca(2+) measurements, and use of pharmacologic activators and inhibitors. Gene silencing was performed using small interfering RNA. Putative receptors of tropisetron were detected by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) and immunofluorescence. The murine model of bleomycin-induced scleroderma was used to assess the antifibrogenic and antifibrotic effects of tropisetron in vivo. Collagen expression in vitro, ex vivo, and in situ was determined by real-time RT-PCR analysis, Western immunoblotting, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and immunohistochemical analysis.. Tropisetron suppressed collagen synthesis induced by transforming growth factor β1 (TGFβ1). This effect was independent of 5-HT(3/4) receptor but was mediated via α7 nicotinic acetylcholine receptor (α7nAChR). Suppression of TGFβ1-induced collagen synthesis occurred via an unknown molecular mechanism not involving modulation of the Smad, cAMP, Akt, c-Jun, or MAPK pathway. In vivo, tropisetron not only prevented skin fibrosis but also reduced the collagen content in established dermal fibrosis induced by bleomycin.. Tropisetron directly reduces collagen synthesis in HDFs via an α7nAChR-dependent mechanism. The antifibrogenic and antifibrotic effects of this agent observed in a mouse model of bleomycin- induced scleroderma indicate the future potential of tropisetron in the treatment of fibrotic diseases such as scleroderma.

Topics: 3T3 Cells; Adult; Aged; alpha7 Nicotinic Acetylcholine Receptor; Animals; Antibiotics, Antineoplastic; Bleomycin; Collagen; Dermis; Disease Models, Animal; Fibroblasts; Fibrosis; Humans; Indoles; Mice; Middle Aged; Receptors, Nicotinic; Scleroderma, Systemic; Serotonin Antagonists; Signal Transduction; Transforming Growth Factor beta1; Tropisetron

There is no known disease-modifying therapy for progressive systemic sclerosis.. It was shown that a patient with secondary fibromyalgia syndrome for whom the development of systemic sclerosis was suspected because of a Raynaud's phenomenon and the presence of SCL-70 antibodies in the serum had experienced a clear pain reduction under treatment with tropisteron, which is the reason why this drug was also used with established systemic sclerosis.. Two patients with progressive systemic sclerosis and positive SCL-70 antibodies were treated for 6 weeks with 5 mg tropisetron daily. Both patients had clear skin symptoms, functional impairments of the locomotor system, and a secondary fibromyalgia syndrome. The skin score and joint motion were checked before, during, and after treatment. In addition, the patients filled in the visual analog scale for pain at these times. At the end of the 6 weeks, the patients showed a clear improvement of the skin score and the movability of various joints as well as a clear reduction of pain. The medication was well-tolerated. Constipation developed in the patients; it could be controlled with laxatives. Follow-up questioning of the patients after 3 months showed that their condition had remained stable.. Two patients with progressive systemic sclerosis showed an improvement of various symptoms under a blockade of the 5-HT3 receptors via tropisetron. The long-lasting effect pointed to immunomodulation. The two cases give cause for clarifying this by means of clinical studies, which should also investigate the question of dosage (possibly 5 mg tropisetron twice daily).

Topics: Adult; Female; Humans; Indoles; Middle Aged; Scleroderma, Systemic; Serotonin 5-HT3 Receptor Antagonists; Serotonin Antagonists; Severity of Illness Index; Tropisetron