Therapeutic Potential Of Edaravone And Its Mechanism 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 in 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, 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. The latest research shows that free radicals play a very important role in the incidence and the development process of rheumatoid arthritis, and may become the treatment of rheumatoid new target. Edaravone (MCI-186) is a new type of free radicals scavenger. Currently it mainly used in the treatment of cerebral ischemia, and the study of the treatment of RA rarely carried out through its free radical scavenging. The aim of this study is to evaluate effect of edaravone on the chicken collagenⅡ-induced arthritis rats from many aspects: arthrocele, malondialdehyde (MDA) in blood plasma, superoxide dismutase (SOD) in blood plasma and concentrations of tumor necrosis factor alpha (TNF-α),nuclear factor-κB (NF-κB) in synovium. Analyz of dependability between edaravone and free radicals, TNF-α, NF-κB, investigating mechanism in treating CIA and value of clinical application.Methods: (1) 30 male wistar rats were randomly averagely divided into five groups. GroupⅠwas normal group; GroupⅡwas model group; GroupⅢwas edaravone low dose group; GroupⅣwas edaravone high dose group; GroupⅤwas lornoxicam group. Except for the rats of normal group, rats of groupⅡ~Ⅴwere injected with the mixture of chicken type II collagenation and Freund's complete adjuvant in the 1/3 position of the inside and middle of the tail to create CIA model. (2) On the 18th day after induction, groupⅢ~Ⅳwere given an intraperitoneal injection with edaravone (3.0 mg/kg.2/d, 6.0 mg/kg.2/d); groupⅤwere given intraperitoneal injection with lornoxicam (4mg/kg.d). (3) The general state was observed after injection. The thickness of right paw and arthritic index was measured in settled time. (4) Kill the rats by every group and blood sampling were centrifugal and frozen to use. (5) Measured the level of SOD, MDA in blood plasma in each group. The genual synovial tissues were acquired and HE staining was done to observe the pathologic change by light microscope. (6) Immunohistochemistry was used to detect the expression of NF-κB and TNF-αin synovial tissues and intensity was analyzed by computerized image system. (6)Use SPSS 13.0 Statistical software to analyse the above-mentioned data.Results:(1) AI: On the 18th day, AI of groupⅡwas significantly higher than the 15th day(P<0.01); and the peak time was on the 21th day. On the same tine, AI of GroupⅢ~Ⅴwere significantly higher than the 15th day(P<0.05). But the peak time was on the 18th day. AI of the three groups (Ⅲ~Ⅴ) were similar (P>0.05). (2) The thickness of right paw: Before the 12th day of induction, the thickness of right paw of GroupⅠ-Ⅴwas almost the same (P>0.05). On the 15st day, the thickness of right paw of groupⅡwas significantly higher than the 12th day(P<0.05); and the peak time was on the 21th day. Paw thickness of GroupⅢ~Ⅴwere significantly higher than GroupⅠon the 15th day(P<0.05); and the peak time was on the 18th day. Paw thickness of GroupⅢ~Ⅴwere significantly lower than GroupⅡon the 21th day(P<0.05); During the whole the thickness of right paw of the three groups(Ⅲ~Ⅴ) were similar (P>0.05). (3) Concentration of SOD,MDA in blood plasma: On the 28th day after induction, concentration of SOD in blood plasma of groupⅡ~Ⅴwere lower than groupⅠ(P<0.01), and that of groupⅢ~Ⅴwere higher than groupⅡ(P < 0.01). Concentration of MDA in blood plasma was the opposite. And the concentration of SOD, MDA of groupⅢ~Ⅴwere similar (P >0.05). (4) IOD of NF-κB, TNF-αof synovium: After induction above-mentioned datas of groupⅡhigher than groupⅠand all of statistic differences were significant (P<0.01). The IOD of NF-κB, TNF-αof groupⅢ~Ⅴwere lower than groupⅡon the 28th day (P<0.01). The statistic differences were significant. But the IOD of NF-κB,TNF-αof groupⅢ~Ⅴwere similar (P>0.05). (5) Analyz of dependability: There was significant linear direct correlation between AI with paw thickness, inverse correlation between SOD with MDA. Paw thickness, MDA in blood plasma, and NF-κB, TNF-αin synovium respectively and directly correlate with each other.Conclusion: (1) Edaravone could exert significantly antioxidation and anti-inflammation action on CIA rats, reduce arthritis index and lighten the thickness of right paw. (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 not better than that of low dosage edaravone, hinting that therapy effect of edaravone may not be depend on dosage. (4) Edaravone could improve arthritis of CIA rats the level of SOD in blood plasma, lighten the level of MDA in blood plasma, TNF-α, NF-κB in synovium tissues of CIA rats. (5) Edaravone could improve arthritis of CIA rats the level of SOD in blood plasma, lighten the level of MDA in blood plasma, TNF-α, NF-κB in synovium was similar with lornoxicam. The prostecdtive efficacy need more research. (6) The level of SOD in plasma reduced, and the level of MDA in plasma and the expression of NF-κB, TNF-αin synovial tissues of CIA rats were obviously increased after induction and significantly correlated with the thickness of right paw, hinting that free radicals, NF-κB, TNF-αeduced important effect in pathological process of RA.