Cuzzocrea Salvatore, Mazzon Emanuela, di Paola Rosanna, Genovese Tiziana, Muià Carmelo, Caputi Achille P, Salvemini Daniela
University of Messina, Messina, Italy.
Arthritis Rheum. 2005 Dec;52(12):3755-60. doi: 10.1002/art.21480.
To investigate the effects of combination therapy with M40403 and methotrexate (MTX) on collagen-induced arthritis (CIA) in rats.
CIA was elicited in Lewis rats that had been assigned to different experimental groups, and the rats were treated daily, starting at the onset of arthritis (day 26), with M40403 2 mg/kg intraperitoneally, MTX 0.15 mg/kg orally, or combination therapy (M40403 2 mg/kg plus MTX 0.015 mg/kg).
The histopathologic features of CIA in type II collagen-challenged rats included erosion of the articular cartilage and bone resorption. Treatment of rats with MTX 0.15 mg/kg orally delayed the development of clinical signs (days 26-35) and improved histologic status in the knee and paw, as clearly demonstrated by a significant reduction in erosion of the articular cartilage at the joint margins and subchondral bone resorption. Furthermore, radiographic evidence of protection against bone resorption and soft tissue swelling was apparent in the tibiotarsal joints of rats treated with MTX 0.15 mg/kg daily. Furthermore, combination therapy with M40403 2 mg/kg plus MTX 0.015 mg/kg exerted significant protection against the development of arthritis, similar to that observed with MTX alone at a dose of 0.15 mg/kg. In contrast, no significant protection was observed in animals treated with M40403 2 mg/kg alone or with MTX 0.015 mg/kg alone.
This study provides the first evidence that M40403, a potent superoxide dismutase mimetic, exerts a significant synergistic effect with MTX in rats with CIA.
研究M40403与甲氨蝶呤（MTX）联合治疗对大鼠胶原诱导性关节炎（CIA）的影响。
将Lewis大鼠诱导出CIA并分配到不同实验组，从关节炎发作（第26天）开始每天进行治疗，腹腔注射2 mg/kg M40403，口服0.15 mg/kg MTX，或联合治疗（2 mg/kg M40403加0.015 mg/kg MTX）。
II型胶原攻击的大鼠CIA的组织病理学特征包括关节软骨侵蚀和骨吸收。口服0.15 mg/kg MTX治疗大鼠可延缓临床症状的发展（第26 - 35天），并改善膝关节和爪子的组织学状况，关节边缘的关节软骨侵蚀和软骨下骨吸收明显减少即可清楚证明。此外，每天用0.15 mg/kg MTX治疗的大鼠胫跗关节有明显的防止骨吸收和软组织肿胀的影像学证据。此外，2 mg/kg M40403加0.015 mg/kg MTX的联合治疗对关节炎的发展有显著的保护作用，类似于单独使用0.15 mg/kg MTX时观察到的效果。相比之下，单独用2 mg/kg M40403或单独用0.015 mg/kg MTX治疗的动物未观察到明显的保护作用。
本研究首次证明，强效超氧化物歧化酶模拟物M40403在患有CIA的大鼠中与MTX发挥显著的协同作用。
