Atividades da clindamicina e de um análogo acetilado em modelos experimentais de inflamação articular.

Abstract

Clindamycin, a lincosamide antimicrobial, in addition to its antimicrobial activity, exhibits activities in models of acute and chronic pain and inflammation, indicating that immunomodulatory effects may contribute to a broader pharmacological potential. In the present study, we investigated the effects of clindamycin and a clindamycin acetylated derivative (CAD) in experimental models of acute joint inflammation and in a microbiological assay. Joint inflammation was induced by intra-articular injection (i.a.) of zymosan (50 μg) or monosodium urate (MSU; 100 μg) in mice. Clindamycin or CAD were administered intraperitoneally (i.p.) 1 h before injection of zymosan or MSU. In addition, the effect of clindamycin administered 1 h after zymosan injection was evaluated. The paw withdrawal threshold, joint diameter, neutrophil recruitment, myeloperoxidase activity, cytokine production such as tumor necrosis factor-α (TNFα), interleukin (IL)-1β, IL-6 and CXCL-1, and the phosphorylation of IκBα were evaluated. An in vitro assay was used to evaluate the effects induced by clindamycin or ACD on TNF-α production by zymosan-stimulated RAW264.7 cells. An in vitro microbiological assay was used to evaluate the activity of clindamycin and CAD. Clindamycin, but not CAD, exhibited activity against Staphylococcus aureus and Salmonella Typhimurium ATCC® strains. Clindamycin administration increased the nociceptive threshold and reduced zymosan-induced joint edema. The activity of clindamycin (400 mg/kg) in the zymosan-induced mechanical allodynia model was attenuated by prior administration of naltrexone, but not by glibenclamide or AM251. Administration of clindamycin (400 mg/kg) or CAD (436 mg/kg) increased the nociceptive threshold and reduced joint edema, neutrophil recruitment, myeloperoxidase activity, TNF-α, IL-1β, IL-6 production, CXCL-1 and the phosphorylation of IκBα. Clindamycin and CAD inhibited the in vitro production of TNFα by RAW264.7 macrophages. The i.a injection of MSU reduced the nociceptive threshold and induced joint edema for 24 h, effects that were reduced by the i.p. administration of clindamycin (400 mg/kg). In summary, we provide additional demonstration of the immunomodulatory effects of clindamycin. These effects may be associated with reduced cytokine production, neutrophil recruitment and NF-κB activity. Such effects were extended to CAD, which exhibited reduced antimicrobial activity. These results indicate that clindamycin derivatives should be investigated as drug candidates that could be useful in the treatment of inflammatory and painful conditions.