Compound 78,A Small Molecule SYK Inhibitor Therapeutic Effect On Collagen-Induced Arthritis In Mice

Rheumatoid arthritis(RA) is a disease whose cause is not clear,with multiple joint disease and symmetry-based non-specific inflammation,the main pathological changes were chronic inflammation and hyperplasia of the synovial joints,synovial hyperplasia edge pannus formation,articular cartilage and subchondral bone is destroyed、absorbed.In the treatment of RA although there has been great progress, but there is still no way to completely cure.Traditional treatment of RA drugs into three categories- non-steroidal anti-inflammatory drugs, corticosteroids and biologics,these drugs can improve symptoms, slow the progression of the disease, but can not completely cure RA, and adverse drug reactions is greater.Therefore, the development of safe and effective new drugs will be one of the main research directions treatment of RA.Our previous work by studying cell experiments show that compound 78 can be suppressed to the TNF-α-induced rheumatoid arthritis synovial fibroblasts proliferation,and to suppress synovial fibroblast cells to secrete inflammatory mediators IL-6 and MMP-3.ObjectiveIn this study,through the perspective from animal experiments,to observe the effect of compound 78 for the secretion of IL-6 、 MMP-3 and synovial hyperplasia,cartilage destruction in CIA mice,to investigate the effect of this compound for the treatment of RA provide the basis for future development of new drug treatment of RA.MethodsUsing CIA mouse model, to divide mice into control group、model group、positive group、the experimental group(high and low concentration), by observing the mouse paw swelling,MIC-CT analysis,HE staining and Safranin O-fast green staining of mouse knee,immunohistochemistry to evaluate this small molecule compound CIA mouse knee joint synovial hyperplasia, cartilage destruction and secrete IL-6,MMP-3 impact.Statistics and calculation methods: All data were dealed with SPSS 19.0 statistical software,the results are expressed in `x±s,groups were compared in two-sample t test,P<0.05 were considered to be statistically significant.Results1、After gavage treatment, the experimental group of mice paw swelling significantly faded,compared with the model group,mice hindlimb average arthritis index noticeable downward trend.2、MIC-CT results showed that the mice in the model group, the knee joint bone destruction is serious,the experimental group of mice knee joint surface have not been completely destroyed, bone still maintains better integrity3、In the result of joint histopathology,By observing HE staining and Safranin-Fast green staining, it can be seen that under the microscope,synovial cell proliferation was not obvious, only a small amount of intra-articular inflammatory cell infiltration,cartilage surface of the knee erosion is not serious, compared with the model group, pathological changes significantly reduced.4 、 In the immunohistochemical results,the experimental group of mice knee was significantly reduced in the secretion of IL-6 and MMP3.Conclusioncompound 78, a small molecule syk inhibitor can effectively alleviate the CIA mouse knee synovial hyperplasia, cartilage destruction mitigate,reduce the secretion of IL-6 、MMP-3 intra-articular.