Salvemini D, Mazzon E, Dugo L, Serraino I, De Sarro A, Caputi A P, Cuzzocrea S
MetaPhore Pharmaceuticals, St. Louis, Missouri 63114, USA.
Arthritis Rheum. 2001 Dec;44(12):2909-21. doi: 10.1002/1529-0131(200112)44:12<2909::aid-art479>3.0.co;2-#.
To investigate the effects of M40403, a synthetic mimetic of superoxide dismutase (SOD), on collagen-induced arthritis (CIA) in rats.
CIA was elicited in Lewis rats by intradermal injection of 100 microl of an emulsion of bovine type II collagen (CII) in Freund's incomplete adjuvant at the base of the tail. A second injection was given on day 21.
Immunization induced an erosive arthritis of the hind paws. Macroscopic evidence of CIA first appeared as periarticular erythema and edema in the hind paws by days 24-26 after the first injection, with a 100% incidence by days 27. Severity progressed over a 35-day period. Radiography revealed soft tissue swelling and focal resorption of bone, together with osteophyte formation in the tibiotarsal joint. Histopathologic features included erosion of the articular cartilage at the joint margins and subchondral bone resorption associated with bone-derived multinucleated cell-containing granulomatous lesions. Treatment with M40403 (2-10 mg/kg/day) starting at the onset of arthritis (day 25) ameliorated the clinical signs on days 26-35 and improved the histologic findings in the joint and paw. Immunohistochemical analysis for nitrotyrosine (a marker of peroxynitrite formation) and poly(ADP-ribose) polymerase (PARP; a nuclear enzyme activated by DNA single-strand damage) revealed positive staining in the inflamed joints of CII-treated rats, suggestive of the formation of peroxynitrite and DNA damage, both of which were markedly reduced by M40403 treatment. Radiographic evidence of protection from bone resorption, osteophyte formation, and soft tissue swelling was apparent in the tibiotarsal joints of M40403-treated rats. Arthritic rats treated with M40403 gained weight at the same rate and to the same extent as normal, nonarthritic rats.
This study shows that a low molecular weight mimetic of SOD, M40403, attenuates the degree of chronic inflammation, tissue damage, and bone damage associated with CIA in the rat, and supports the possible use of SOD mimetics as therapeutic agents for the management of chronic diseases such as rheumatoid arthritis.
研究超氧化物歧化酶（SOD）合成模拟物M40403对大鼠胶原诱导性关节炎（CIA）的影响。
在Lewis大鼠尾根部皮内注射100微升牛II型胶原（CII）与弗氏不完全佐剂的乳剂，诱发CIA。第21天进行第二次注射。
免疫诱导后出现后爪侵蚀性关节炎。首次注射后24 - 26天，CIA的宏观表现首先为后爪关节周围红斑和水肿，到第27天发病率达100%。严重程度在35天内逐渐加重。X线检查显示软组织肿胀、骨局部吸收以及胫跗关节骨赘形成。组织病理学特征包括关节边缘关节软骨侵蚀和与含骨源性多核细胞的肉芽肿性病变相关的软骨下骨吸收。从关节炎发作（第25天）开始用M40403（2 - 10毫克/千克/天）治疗，可改善第26 - 35天的临床症状，并改善关节和爪子的组织学表现。对硝基酪氨酸（过氧亚硝酸盐形成的标志物）和聚（ADP - 核糖）聚合酶（PARP；一种由DNA单链损伤激活的核酶）的免疫组织化学分析显示，在CII处理大鼠的炎症关节中有阳性染色，提示过氧亚硝酸盐形成和DNA损伤，而M40403治疗可使二者明显减少。在M40403治疗大鼠的胫跗关节中，有明显的X线证据表明可防止骨吸收、骨赘形成和软组织肿胀。用M40403治疗的关节炎大鼠体重增加的速率和幅度与正常非关节炎大鼠相同。
本研究表明，SOD的低分子量模拟物M40403可减轻大鼠CIA相关的慢性炎症、组织损伤和骨损伤程度，并支持SOD模拟物可能作为治疗类风湿关节炎等慢性疾病的治疗药物。
