Inibição dos efeitos hiperalgésicos e inflamatórios por análogos híbridos triazólicos de 1,4-diaril-1,2,3-triazol neolignana-celecoxibe em artrite experimental

Abstract

Rheumatoid arthritis (RA) is a chronic, symmetric, and progressive autoimmune disease that causes damage to cartilage. Anti-inflammatories are among the most used medications for the management of RA, however, they can have important side effects such as renal and hepatic toxicity, and gastrointestinal and cardiovascular disorders. In the search for safer drug prototypes, triazole analogs derived from the lignans Grandisin and Veraguensin hybridized with celecoxib, called Lasquim (L), were synthesized and associated with sulfonamide (L15) or carboxylic acid (L18). A study published by our group showed that the analogs (L15) and (L18) exhibited anti-inflammatory activity in an acute model of inflammation, inhibited the expression of P-selectin related to platelet activation, and did not induce gastric ulcers, minimizing the related deleterious effects to anti-inflammatories available on the market. In continuation, the present study evaluated the anti-inflammatory effects of these analogs in an experimental model of chronic inflammation, through the evaluation of mechanical hyperalgesia, joint edema, recruitment of leukocytes to the joint, and histological evaluation of the joint capsule. Furthermore, the effect of analogs on the cellular functions of macrophages was evaluated, through the evaluation of cytotoxicity, the release of hydrogen peroxide (H202), and the production of nitric oxide (NO). Macrophage spreading and phagocytosis of these cells were also evaluated. Results were expressed as mean ± S.E.M., ANOVA, Bonferroni (p <0.05). For in vivo experiments, male Swiss mice weighing 25 to 30 g were used, distributed in the saline (sham), water, L15, and L18 (1, 3, and 10 mg/Kg) and celecoxib (10 mg/Kg) groups. Sixty minutes after pretreatment (v.o.), the mice's knee joint received an intra-articular (i.a.) injection of zymosam (200 µg/10µL 0.9% NaCl). Pretreatment with L15 and L18 reduced mechanical hyperalgesia, joint edema, and the influx of leukocytes into the joint cavity after different periods of stimulation. In the histological analysis of the joints of animals treated with L15 and L18, they reduced damage to the joint capsule and there was no formation of rheumatoid pannus. The effects observed were not dose-dependent and L15 and L18 were as effective as celecoxib in the trials carried out. Additionally, in vitro tests, L15 and L18 were not cytotoxic, reduced the macrophage spreading and production of NO and H202 and, L15 decreased phagocytosis. It was concluded that the L15 and L18 analogs reduced the inflammatory parameters of experimental arthritis, and reduced damage to cartilage and joint capsule. Moreover, the analogs demonstrated in vitro reduction of the functions of macrophages, relevant cells in chronic inflammatory processes. Therefore, L15 and L18 can be considered promising therapeutic prototypes for the treatment of inflammatory diseases, such as rheumatoid arthritis.

Keywords: Selective COX-2 inhibitors; Chronic inflammation; Macrophages; In vitro