Therapeutic Potential Of Edaravone And Its Effect In Proinflammatory Cytokines In Collagen-induced Arthritis Rats

Objective: Rheumatoid Arthritis(RA) is a kind of chronic, systemic, autoimmune disease, and is characterized by symmetric and destructive arthrosynovitis, The process of pathological changes is characterized by persistence and repetition. The disease progresses gradually will result multiple system dysfunction and eventually leading to cartilage and bone destruction.The etiology of RA is still unclear. However, A large number of studies clearly indicate that the important reasons perhaps include:activation of many kinds of immunocytes, participation of cell factors and mediators of inflammation,the imbalance between synovial cell hyperplasy and apoptosis ,and formation of pannus. Now for RA patients, internal and overseas doctors have not find an ideal medicine. because of the traditional anti-rheumatic drugs side effects or curative effect lowness and biological agents expensive cost, so it is imperative to find a medicine with well match between price and effect. edaravone as a clinically available free radical scavenger in Japan, is confirmed to be beneficial in the acute stage of stroke. In addition to it,s free radical - scavenger ring properties, edaravone exert a number of so-called pleiotropic, including suppression of nuclear factor-kappa B and Apoptosis -accommodation action. internal reports on RA therapy is unusual. The collagen-induced arthritis of rats induced by fowl type II collagen are widely considered having a similar pathologic change in arthritis compared to RA, The aim of this study is to evaluate effect of edaravone on the collagen-induced arthritis of rats from many aspects:arthrocele, concentrations ofNF-κB and Fas/FasL in synovium, Analyz of dependability between edaravone and the apoptosis of synovium cell,Fas FasL,NF-κB is used to investigat mechanism in treating RA and value of clinical application.Methods: (1)30 male Wistar rats were randomly divided into five groups. GroupⅠwas normal group;GroupⅡwas model group;GroupⅢwas high dose edaravone group;GroupⅣwas low dose edaravone group;GroupⅤwas lornoxicam group. Except for the rats of normal group, Rats of groupⅡ～Ⅴwere injected with 0.1ml fowl type II collagenation in the 1/3 position of the inside and middle of the tail.(2)On the 18th day after induction, groupⅢ～Ⅳwere given an intraperitoneal injection with edaravone (3.0mg/kg 2/d,6.0mg/kg 2/d);groupⅤwere given intraperitoneal injection with Lornoxicam (4.0mg/kg.d). (3)The general state was observed after injection , The volume of right foot and arthritic index was measured in settled time. (4)The rats were killed by every group and blood sampling were centrifugal and frozen to use. The genual synovial tissues were acquired and HE staining was done to observe the pathologic change by light microscope.(5) flow cytomet ric analysis;was used to detect the number of Apoptosis cell in synovial tissues and the expression of Fas/FasL.(6)Immunohistochemistry was used to detect the expression of NF-κB in synovial tissues and intensity was analyzed by computerized image system. (7)Use SPSS 13.0 Statistical software to analyse the above-mentioned data.Results:(1) AI: Before the 12nd day of induction, AI of GroupⅠ～Ⅴwas almost the same (P>0.05).On the 18th day , AI of groupⅡwas significantly higher than that on the 15th day(P<0.05);and the peak time was on the 21st day. On the 18th day ,AI of GroupⅢ～Ⅴwere significantly higher than the 15th day(P<0.05);But the peak time was on the 18st day.AI of the three groups(Ⅲ～Ⅴ) were similar (P>0.05). (2) The thickness of right foot : Before the 12nd day of induction, the thickness of right foot of GroupⅠ～Ⅴwas almost the same (P>0.05).On the 15st day ,the thickness of right foot of groupⅡwas significantly higher than groupⅠ(P<0.05);and the peak time was on the 18th and 21st days. AI of GroupⅢ～Ⅴwere significantly higher than GroupⅠthe 15th day(P<0.05);and the peak time was on the 18th～21st day. During the whole the thickness of right foot of the three groups(Ⅲ～Ⅴ) were similar (P>0.05). (3)Apoptosic rate of cell : There is no difference between GroupⅡand GroupⅠon the 28th day.The apoptosic rate of cell of groups(Ⅲ～Ⅴ) were higher than both GroupⅡand GroupⅠ.There is no difference among the three groups(Ⅲ～ Ⅴ).(4)IOD of NF-κB of synovium,and histopathological integration of synovium: After induction above-mentioned datas of groupⅡhigher than groupⅠand all of statistic differences were significant.The IOD of NF-κB of groupⅢ～Ⅴwere lower than groupⅡon the 28th day, The statistic differences were significant. But the IOD of NF-κB of groupⅢ～Ⅴwere similar (5) The expresion of Fas in synovium: The expresion of Fas in synovium of groupⅡis higher than GroupⅠon the 28th day. The expresion of Fas in synovium of groups(Ⅲ～Ⅴ) were higher than both GroupⅡand GroupⅠ.There is no difference among the three groups(Ⅲ～Ⅴ). (6)The expresion of FasL in synovium: the expresion of FasL in synovium of GroupⅡis lower than GroupⅠon the 28th day.The expresion of FasL in synovium of groups(Ⅲ～Ⅴ) were higher than both GroupⅡand GroupⅠ.There is no difference among the three groups(Ⅲ～Ⅴ). (7) Analyz of dependability:There was significant linear direct correlation between AI with the thickness of right foot, NF-κB,the apoptosic rate of cell,Fas and FasL in synovium respectively and directly correlate with the thickness of right foot and histopathological integration of synovium.Conclusion:(1)Edaravone could exert significantly anti-inflammation action on CIA rats, reduce arthritis index and lighten the thickness of right foot. (2)Edaravone could lighten Synovium swelling and reduce synovium lining layer cell hyperplasia, hinting that edaravone could defer the course of diseases development. (3)The therapy effect of high dosage edaravone were no better than that of low dosage edaravone, hinting that therapy effect of edaravone may not be depend on dosage. (4)Edaravone could reduce expression of NF-κB in synovial tissues of CIA rats. And up-regulation the expression of Apoptosis Fas, FasL in synovial tissues of CIA rats. (5)Edaravone could lighten arthritis of CIA rats and the expression of NF-κB in synovial tissues of CIA rats.the level of NF-κB in synovial tissue was similar with Lornoxicam, The prostecdtive efficacy need more rearch.