Platelet activating factor (PAF) is a potent mediator of allergic and inflammatory reactions in different pathological conditions. During recent years there has been increasing evidence that PAF can play an important role in the pathogenesis of
arthritis. The PMN
proteinases make an important contribution to the final tissue joint destruction in
arthritis. In a rabbit model of acute
crystal arthritis, we have compared the anti-inflammatory effect of two new molecules:
BN 50727 with anti-PAF activity, and
BN 50548 an inhibitor of PMN
proteinases. These molecules were administered dissolved in
DMSO at doses of 6 mg/kg three times daily i.p., beginning 24 h before the induction of
arthritis. Compared with the untreated animals those receiving the drugs, presented a significant diminution in: (1) the synovial fluid volume; (2) the amount of cells infiltrating the joint cavity and the synovial membrane; and (3) the
PGE2 concentration. Furthermore, in both groups of treated rabbits there was a significant decrease in synovial
IL-6 concentration and in
C-reactive protein serum levels and an important decline of histopathological score. The treatment with
BN 50548 induced a significant reduction of TNF levels in the synovial fluid vs
DMSO-treated and untreated rabbits. These results further strengthen that in an acute
experimental arthritis model, molecules with capacity to antagonize the in vivo action of PAF have an anti-inflammatory effect reflecting an important role for this mediator in the pathogenesis of
arthritis. We have also seen that an inhibitor of
proteinases is capable of improving the joint
inflammation apparently through a decrease in
tumor necrosis factor (TNF) and
interleukin-6 (IL-6) synovial levels. Furthermore, the
proteinase inhibitor treatment preserves the loss of articular
proteoglycan content, in an acute
arthritis model. In conclusion,
BN 50727 and
BN 50548, two compounds with PAF antagonist and antiproteinase activity, respectively exert an anti-inflammatory effect in an experimental model of acute
urate crystal arthritis, probably due to a decrease in
TNF alpha and
IL-6 synthesis.