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Abstract
Gouty arthritis is characterized by an intense inflammatory response to monosodium urate crystals (MSU), which induces severe pain and reduction in the life quality of patients. Trans-Chalcone (1,3-diphenyl-2-propen-1-one) is a flavonoid precursor presenting biological activities such as anti-inflammatory and antioxidant proprieties. Thus, the aim of this work was to evaluate the protective effects of trans-Chalcone in experimental gout arthritis in mice. Mice were treated with trans-Chalcone (3, 10, or 30 mg/kg, per oral) or vehicle (Tween 80 20% plus saline) 30 min before intra-articular injection of MSU (100 μg/knee joint, intra-articular). We observed that trans-Chalcone inhibited MSU-induced mechanical hyperalgesia, edema, and leukocyte recruitment (total leukocytes, neutrophils, and mononuclear cells) in a dose-dependent manner. Trans-Chalcone also decreased inflammatory cell recruitment as observed in Hematoxylin and Eosin (HE) staining and the intensity of fluorescence of LysM-eGFP+ cells in the confocal microscopy. Trans-Chalcone reduced MSU-induced oxidative stress as observed by an increase in the antioxidant defense [Glutathione (GSH), Ferric Reducing (FRAP), and 2,2’-Azinobis-3-ethylbenzothiazoline 6-sulfonic acid (ABTS assays)] and reduction in reactive oxygen and nitrogen species production [superoxide anion (NBT assay) and nitrite (NO assay)]. Furthermore, it reduced in vivo MSU-induced interleukin-1β (IL-1β), Tumor necrosis factor-α (TNF-α), and IL-6 production, and increased Transforming growth factor-β (TGF-β) production. Importantly, trans-Chalcone reduced nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation and thereby the mRNA expression of the inflammasome components Nlrp3 (cryopyrin), Asc (apoptosis-associated speck-like protein containing a CARD), Pro-caspase-1 and Pro-IL-1β. In vitro, trans-Chalcone reduced the MSU-induced release of IL-1β in lipopolysaccharide (LPS)-primed macrophages. Therefore, the pharmacological effects of trans-Chalcone indicate its therapeutic potential as an analgesic and anti-inflammatory flavonoid for the treatment of gout.
Highlights
Gout is a painful inflammatory disease caused by the overproduction of uric acid, which forms deposits and crystallizes as monosodium urate (MSU) in articular and periarticular tissues (Rees et al, 2014; Fattori et al, 2016)
Severe pain and swelling around the joint are the most clinical findings after acute gout in humans causing disability to the patients (Amaral et al, 2012; Ruiz-Miyazawa et al, 2017). Considering these features, in the first set of experiments we addressed whether trans-Chalcone would inhibit MSUinduced knee joint mechanical hyperalgesia and edema within 15 h after monosodium urate crystals (MSU) injection
By using LysM-eGFP mice as another approach to investigate MSU-induced neutrophil recruitment, we show that trans-Chalcone reduced the infiltration of LysM-eGFP+ cells that includes neutrophils and monocytes/macrophages (Figures 2D,E), as observed by reduced intensity of fluorescence (Figures 2D,E)
Summary
Gout is a painful inflammatory disease caused by the overproduction of uric acid, which forms deposits and crystallizes as monosodium urate (MSU) in articular and periarticular tissues (Rees et al, 2014; Fattori et al, 2016). The management of gout flares lies on the use of non-steroidal anti-inflammatory drugs (NSAIDs), colchicine, corticoids, or biological agents (Rees et al, 2014; Dalbeth et al, 2016). The use of these drugs lack safety in patients with comorbidities (NSAIDs), often cause severe side effects (NSAIDs, colchicine, and corticoids), present high cost (biological agents), or possess non-satisfactory analgesic effects in some patients (Rees et al, 2014; Dalbeth et al, 2016)
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