Abstract
The present study aimed to test the anti-inflammatory and xanthine oxidase inhibitory activities of two synthesized molecules and compare them to routinely prescribed nonsteroidal anti-inflammatory drugs (NSAIDs), such as diclofenac and the serum urate-lowering drug, allopurinol. The anti-inflammatory effects of the designed compounds (A and B) were evaluated in carrageenan (CAR)-induced paw edema in mice. The levels of nitric oxide and myeloperoxidase activity were measured in paw skin using biochemical methods. Additionally, prostaglandin E2 (PGE2), C-reactive protein (CRP), cyclooxygenase-2 (Cox-2), tumor necrosis factor-α (TNFα), interleukin (IL)-1β, IL-2 and IL-10, and monocyte chemoattractant protein-1 (MCP1) were assessed by enzyme-linked immunosorbent assay (ELISA). The expression of inflammation-related genes was confirmed by real-time qPCR. The expression of inducible nitric oxide synthase (iNOS) and nuclear factor-kappa B (NF-κB) were estimated using immunohistochemistry, and xanthine oxidase inhibitory activity was evaluated using an in vitro assay. The results revealed that compounds A and B decreased inflammation, as was observed by a reduction in the elevation of all the tested markers. In addition, the tested compounds markedly decreased paw swelling, mobilization of inflammatory cells, iNOS-, and NF-κB-immunoreactive cells in a mouse model of paw edema. Interestingly, both compounds were potent xanthine oxidase inhibitors as well as Cox inhibitors with higher activity in favor of compound B providing potential dual acting series of anti-hyperuricemic and anti-inflammatory therapeutic agents.
Highlights
Inflammation is an important adaptive response for defense against harmful stimuli, such as infection, tissue stress, and injury [1]
We observed that compound B reduced paw edema better than a 20 mg/kg dose of diclofenac. These results indicate that the tested compounds possess anti-inflammatory activity, and they can modulate the inflammatory mediators in CAR-induced acute inflammation
We showed an anti-inflammatory effect of Compounds A and B by evaluating inducible nitric oxide synthase (iNOS) and NF-κB expression in paw tissues
Summary
Inflammation is an important adaptive response for defense against harmful stimuli, such as infection, tissue stress, and injury [1]. The two tested compounds, designated compound A and compound B are hybrid molecules with two active sites and are structural analogs to both diclofenac and febuxostat Both compound A and compound B showed major inhibition of Cox-2, CRP, IL-1β, IL-2, iNOS, NO, MPO, MCP1, TNF-α, and PGE2, and showed a significant anti-inflammatory effect compared with diclofenac (p < 0.5) (Figure 7). Both compound A and compound B showed major inhibition of Cox-2, CRP, IL-1β, IL-2, iNOS, NO, MPO, MCP1, TNF-α, and PGE2, and showed a significant anti-inflammatory effect compared with diclofenac WFiigthurdeicl7o.feHnaeac.tmap showing the effect of each tested compound on the tested inflammatory
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