Conte Fernando P, Ferraris Fausto K, Costa Thadeu E M M, Pacheco Patricia, Seito Leonardo N, Verri Waldiceu A, Cunha Fernando Q, Penido Carmen, Henriques Maria G
Laboratório de Farmacologia Aplicada, Farmanguinhos, Fundação Oswaldo Cruz, Rio de Janeiro 21041-250, Brazil.
Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina 86057-970, Brazil.
Molecules. 2015 Feb 3;20(2):2636-57. doi: 10.3390/molecules20022636.
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.
格杜宁是一种从楝科植物中提取的天然柠檬苦素，此前在过敏性炎症的实验模型中被描述为一种抗炎化合物。在此，我们报告了格杜宁在C57BL/6小鼠由酵母聚糖（500μg/关节腔；关节内注射）诱导的急性关节炎症模型中的抗炎和镇痛作用。用格杜宁（0.005 - 5mg/kg）腹腔内（i.p.）预处理可减轻酵母聚糖诱导的小鼠膝关节水肿形成、中性粒细胞积聚和痛觉过敏，这是由于前内皮素原-1 mRNA表达降低以及白三烯B4、前列腺素E2、肿瘤坏死因子-α和白细胞介素-6的产生减少。在刺激后1小时和6小时用格杜宁（0.05mg/kg；i.p.）对小鼠进行治疗也可减轻关节炎症，通过恢复水肿形成、中性粒细胞积聚以及脂质介质、细胞因子和内皮素的产生。此外，格杜宁在体外直接调节中性粒细胞和巨噬细胞的功能。用格杜宁（100μM）预孵育中性粒细胞可损害由不同刺激引发的形态变化、对内皮细胞的粘附、趋化性和脂质体形成。用格杜宁预处理巨噬细胞可损害细胞内钙动员、一氧化氮产生、诱导型一氧化氮合酶表达，并诱导抗炎伴侣热休克蛋白70的表达。我们的结果表明，格杜宁对酵母聚糖诱导的炎症膝关节具有显著的抗炎和镇痛作用，可调节不同的细胞群体。
