Artikel
Oxacyclododecindione – new promising results in the treatment of SLE
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Autoren
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Jenny Henke
- Universitätsklinikum Mainz, Institut für Pharmakologie, Mainz
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Julia Menke
- Universitätsklinikum Mainz, I. Medizinische Klinik und Poliklinik, Schwerpunkt Rheumatologie und klinische Immunologie, Mainz
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Gerhard Erkel
- Institut für Biotechnologie, Technische Universität Kaiserslautern, Kaiserslautern
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Hartmut Kleinert
- Universitätsklinikum Mainz, Institut für Pharmakologie, Mainz
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Andrea Pautz
- Universitätsklinikum Mainz, Institut für Pharmakologie, Mainz
| Veröffentlicht: | 12. September 2014 |
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Gliederung
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Background: Oxacyclododecindione (Oxa) is a novel macrocyclic lacton isolated from the imperfect fungus Exserohilum rostratum. In recent studies, Oxa showed a high anti-inflammatory, anti-angiogenic and anti-fibrotic activity in in-vitro and in-vivo models. The aim of our study was to investigate the benefit of Oxa treatment on renal function and to identify further target molecules to decipher the molecular mechanism of Oxa.
Methods: In-vivo we tested Oxa in female lupus prone MRL-Faslpr mice. Therefore we treated the mice with Oxa (1mg/kg) every other day by intraperitoneally injection over a period of five weeks. The effects of the substance were analyzed in comparison to a control group, which was treated with PBS/EtOH (10%).
Results: In line with the already shown anti-inflammatory properties of Oxa in MRL-Faslpr mice, we can demonstrate that the kidney function, determined by proteinuria, IgG and collagen deposition, was improved by Oxa treatment as well. In addition, we detected less circulating dsDNA antibodies under Oxa treatment. The analysis of several miRNAs as possible target molecules of Oxa showed an increased expression of the SLE associated miRNAs 19a, 29c and 369. For analyzing the mode of action, the impact of Oxa on p38 MAPK and STAT1 was examined. We found no influence of Oxa on STAT1 activation, however, phosphorylation of the p38 MAPK was modified. Further, we found in mRNA decay experiments an influence of Oxa on the mRNA stability of proinflammatory cytokines. In course of increased drug interaction, we also examined the impact of Oxa on the activity of Cyp3A4. In in-vitro assay we could not detect any significant influence of Oxa on Cyp3A4.
Conclusion: Our analyses provide evidence that Oxa is a new promising anti-inflammatory compound which has positive effects in the SLE model of MRL-Faslpr mice. However, the identification of the mode of action of Oxa is still at the beginning. In the future, this substance may serve as lead structure for the development of new therapeutics for the treatment of chronic inflammatory as well as fibrotic diseases.
