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 (100 μg/10 μL, intra-articular). Knee joint withdrawal threshold and
edema were evaluated using electronic von Frey and caliper, respectively, 1-15 h 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 5 h after stimulation with MSU crystals. For these experiments, BMDMs were either treated or pre-treated with
budlein A at concentrations of 1, 3, or 10 μg/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.