Anti-inflammatory effect of a PAF receptor antagonist and a new molecule with antiproteinase activity in an experimental model of acute urate crystal arthritis.
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.
Miguélez
R
R
Inflammation Unit, Fundación Jiménez Díaz, Madrid Spain.
Palacios
I
I
Navarro
F
F
Gutierrez
S
S
Sanchez-Pernaute
O
O
Egido
J
J
González
E
E
Herrero-Beaumont
G
G
D000208:Acute Disease; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D015210:Arthritis, Gouty / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001381:Azepines / Q000627:therapeutic use*; D002097:C-Reactive Protein / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D007192:Indenes / Q000627:therapeutic use*; D015850:Interleukin-6 / Q000378:metabolism; D007596:Joints / Q000473:pathology; D010972:Platelet Activating Factor / Q000378:metabolism; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D011480:Protease Inhibitors / Q000627:therapeutic use*; D011817:Rabbits; D011897:Random Allocation; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D013582:Synovial Fluid / Q000737:chemistry / Q000378:metabolism; D058924:Thienopyridines; D014230:Triazoles / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014527:Uric Acid
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001381:Azepines; C091335:BN 50548; D007192:Indenes; D015850:Interleukin-6; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D011480:Protease Inhibitors; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D058924:Thienopyridines; D014230:Triazoles; D014409:Tumor Necrosis Factor-alpha; C039351:platelet activating factor receptor; D014527:Uric Acid; D002097:C-Reactive Protein; D015232:Dinoprostone; C067429:Setipafant