Abstract
Gedunin, a natural limonoid from Meliaceae species, has been previously described as an antiinflammatory compound in experimental models of allergic inflammation. Here, we report the antiinflammatory and antinociceptive effects of gedunin in an acute model of articular inflammation induced by zymosan (500 μg/cavity; intra-articular) in C57BL/6 mice. Intraperitoneal (i.p.) pretreatment with gedunin (0.005–5 mg/kg) impaired zymosan-induced edema formation, neutrophil accumulation and hypernociception in mouse knee joints, due to decreased expression of preproET-1 mRNA and production of LTB4, PGE2, TNF-α and IL-6. Mouse post-treatment with gedunin (0.05 mg/kg; i.p.) 1 and 6 h after stimulation also impaired articular inflammation, by reverting edema formation, neutrophil accumulation and the production of lipid mediators, cytokines and endothelin. In addition, gedunin directly modulated the functions of neutrophils and macrophages in vitro. The pre-incubation of neutrophil with gedunin (100 µM) impaired shape change, adhesion to endothelial cells, chemotaxis and lipid body formation triggered by different stimuli. Macrophage pretreatment with gedunin impaired intracellular calcium mobilization, nitric oxide production, inducible nitric oxide synthase expression and induced the expression of the antiinflammatory chaperone heat shock protein 70. Our results demonstrate that gedunin presents remarkable antiinflammatory and anti-nociceptive effects on zymosan-induced inflamed knee joints, modulating different cell populations.
Highlights
Articular inflammation is a major clinical symptom of acute and chronic joint diseases, such as rheumatoid arthritis, osteoarthritis and gout
The intra-articular (i.a.) injection of zymosan (500 μg/cavity) into mouse knee joints induced an inflammatory response within 6 h, characterized by significant edema formation and massive leukocyte accumulation, mainly due to neutrophil influx (Figure 1A–C), as previously demonstrated [6,8]
(36% and 41% of inhibition, respectively). Corroborating this data, histological analysis of knee joint tissues from zymosan-stimulated mice revealed an intense neutrophil accumulation within 6 h (Figure 1D), when compared to control group (Figure 1E), that was prevented by dexamethasone
Summary
Articular inflammation is a major clinical symptom of acute and chronic joint diseases, such as rheumatoid arthritis, osteoarthritis and gout. Zymosan-induced articular inflammation is considered a model of arthritis that develops into a chronic stage in mice and rats [4,5] It is characterized by periarticular edema, neutrophil and mononuclear cell infiltration, synovial hypertrophy, pannus formation and pain [4,5], which are mediated by the massive local generation of protein and lipid inflammatory mediators, including tumor necrosis factor (TNF)-α, interleukin (IL)-1-β, IL-6 and leukotriene (LT)B4 [6,7]. Once in the tissue, activated neutrophils cause tissue damage via the release of reactive oxygen species (ROS) and proteases, such as matrix metalloproteinase (MMP)-8, MMP-9, neutrophil elastase and cathepsin G into the synovial fluid and joints [9,10,11] In addition to their cytotoxic properties, neutrophils of immune cells contribute to the pathology of joint diseases by orchestrating the inflammatory response, modulating the functions in T lymphocytes and macrophages, via the production of chemokines and cytokines [12,13]. We demonstrate that gedunin suppresses articular inflammation in an experimental model of zymosan-induced acute articular inflammation, impairing articular neutrophil influx, edema formation, hypernociception and the production of pro-inflammatory mediators, including cytokines and lipid mediators
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