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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Pharmacol. | doi: 10.3389/fphar.2018.01076

Budlein A, a sesquiterpene lactone from Viguiera robusta, alleviates pain and inflammation in a model of acute gout arthritis in mice

  • 1Department of Pathology, Biological Sciences Center, Universidade Estadual de Londrina, Brazil
  • 2Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Brazil
  • 3Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Brazil

Background: gout is the most common inflammatory arthritis worldwide. It is a painful inflammatory disease induced by the deposition of monosodium urate (MSU) crystals in the joints and peri-articular tissues. Sesquiterpene lactones (SLs) are secondary metabolite biosynthesized mainly by species from the family Asteraceae. It has been demonstrated that SLs present anti-inflammatory, analgesic, antitumoral, antiparasitic, and antimicrobial activities. In this study, we aimed at evaluating the efficacy of the SL budlein A in a model of acute gout arthritis in mice. Methods: experiments were conducted in male Swiss or male LysM-eGFP mice. Animals were treated with budlein A (1 or 10 mg/kg) or vehicle 30 min before stimulus with MSU (100µg/10µL, intra-articular). Knee joint withdrawal threshold and edema were evaluated using electronic von Frey and caliper, respectively, 1-15h after MSU injection. Leukocyte recruitment was determined by counting cells (Neubauer chamber), H&E staining, and using LysM-eGFP mice by confocal microscopy. Inflammasome components, Il-1β, and Tnf-α mRNA expression were determined by RT-qPCR. IL-1β and TNF-α production (in vitro) and NF-κB activation (in vitro and in vivo) were evaluated by ELISA. In vitro analysis using LPS-primed bone marrow-derived macrophages (BMDMs) was performed 5h after stimulation with MSU crystals. For these experiments, BMDMs were either treated or pre-treated with budlein A at concentrations of 1, 3, or 10μg/mL. Results: we demonstrated that budlein A reduced mechanical hypersensitivity and knee joint edema. Moreover, it reduced neutrophil recruitment, phagocytosis of MSU crystals by neutrophils, and Il-1β and Tnf-α mRNA expression in the knee joint. In vitro, budlein A decreased TNF-α production, which might be related to the inhibition of NF-κB activation. Furthermore, budlein A also reduced the IL-1β maturation, possibly by targeting inflammasome assembly in macrophages. Conclusion: budlein A reduced pain and inflammation in a model of acute gout arthritis in mice. Therefore, it is likely that molecules with the ability of targeting NF-κB activation and inflammasome assembly, such as budlein A, are interesting approaches to treat gout flares.

Keywords: Knee Pain, joint pain, gout treatment, Rheumatic disease, experimental arthritis, NLRP3 inflammasome, Analgesia, sesquiterpene lactones

Received: 16 Jun 2018; Accepted: 05 Sep 2018.

Edited by:

Luis Cláudio Nascimento Da Silva, Universidade Ceuma, Brazil

Reviewed by:

Lorenzo Di Cesare Mannelli, Università degli Studi di Firenze, Italy
Francisco R. Nieto, Deparment of Pharmacology, University of Granada, Spain  

Copyright: © 2018 Fattori, Zarpelon, Staurengo-Ferrari, Borghi, Zaninelli, Da Costa, Alves-Filho, Cunha, Cunha, Casagrande, Arakawa and Verri. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Waldiceu A. Verri, Universidade Estadual de Londrina, Department of Pathology, Biological Sciences Center, Londrina, 86051990, Parana, Brazil, waldiceujr@yahoo.com.br