Monoartrite induzida por adjuvante completo de Freund em ratos Holtzman e avaliação dos efeitos induzidos pelo tratamento crônico com tiamina ou riboflavina

Abstract

Preclinical models of rheumatoid arthritis (RA) in rodents have been widely used to investigate the disease mechanisms and also to screen new drugs. Similarities with the human disease and predictive value for efficacy and safety are important criteria to choose a preclinical model of RA. Arthritis induced by adjuvant in rats is a preclinical model of RA with a well established predictive value for efficacy of antiarthritic drugs. Two injections of complete Freund adjuvante (CFA; Mycobacterium tuberculosis, 1 mg/mL) in the first day (one intradermal injection of 100 ìL into the tail base and one intraplantar injection of 100 ìL into the right paw) followed by a third injection in the second day (a intradermal injection of 100 ìL into the tail base) in female Holtzman rats induced an immediate and long lasting (21 days) localized periarticular inflammation.The monoarthritic model allowed to identify characteristic changes of the early phase of RA in humans, including edema, mechanical allodynia, panniculitis, synovitis, neoangiogenesis and increase of myeloperoxidase activity, without systemic disease that resulted in severe animal suffering. Body temperature increase was observed only after the second injection of CFA. As riboflavin and thiamine activities have been demonstrated in acute models of pain and inflammation, their effects on the mechanical allodynia and edema in the experimental model were investigated. Riboflavin (125, 250 or 500 mg/Kg) or thiamine (150, 300 or 600 mg/Kg) were administered per os, twice daily, throughout the experimental period. Riboflavin reduced neither paw edema nor mechanical allodynia. Thiamine did not change paw edema, but dose-dependently inhibited the mechanical allodynia on days 6 and 12 of the experimental period. The effects induced by the association of thiamine (600 mg/Kg) or riboflavin (500 mg/kg) with dexamethasone (0.5 mg/Kg, per os) on the mechanical allodynia and paw edema induced by the injections of CFA were also investigated. Mechanical allodynia was inhibited neither by dexamethasone nor by the association of riboflavin with dexamethasone. The association of thiamine with dexamethasone, when compared with each drug, induced a greater antiedematogenic effect. In conclusion, the results of the present study demonstrate that the model of monoarthritis induced by CFA in Holtzman rats is reproducible, allowing to identify RA typical inflammatory changes such as long lasting synovitis, panniculitis, neoangiogenesis, paw edema and mechanical allodynia. Advantages of an experimental model of RA in which the animals develop monoarthritis, but not polyarthritis, include the possibility of identifying characteristic signs of the disease in a single joint, with reduced impact over the physiological functions, minor animal suffering and greater probability of detecting effects induced by drug candidates. The results also indicate that riboflavin and mainly thiamine may be useful in the treatment of RA patients, especially in association with other drugs with established efficacy.