Synergistic interaction between methotrexate and a superoxide dismutase mimetic: Pharmacologic and potential clinical significance

Salvatore Cuzzocrea, Emanuela Mazzon, Rosanna Di Paola, Tiziana Genovese, Carmelo Muià, Achille P. Caputi, Daniela Salvemini

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Abstract

Objective. To investigate the effects of combination therapy with M40403 and methotrexate (MTX) on collagen-induced arthritis (CIA) in rats. Methods. 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). Results. 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. Conclusion. This study provides the first evidence that M40403, a potent superoxide dismutase mimetic, exerts a significant synergistic effect with MTX in rats with CIA.

Original languageEnglish
Pages (from-to)3755-3760
Number of pages6
JournalArthritis and Rheumatism
Volume52
Issue number12
DOIs
Publication statusPublished - Dec 2005

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Methotrexate
Superoxide Dismutase
Experimental Arthritis
Bone Resorption
Articular Cartilage
Arthritis
Joints
Collagen Type II
imisopasem manganese
Knee
Therapeutics

ASJC Scopus subject areas

  • Immunology
  • Rheumatology

Cite this

Synergistic interaction between methotrexate and a superoxide dismutase mimetic : Pharmacologic and potential clinical significance. / Cuzzocrea, Salvatore; Mazzon, Emanuela; Di Paola, Rosanna; Genovese, Tiziana; Muià, Carmelo; Caputi, Achille P.; Salvemini, Daniela.

In: Arthritis and Rheumatism, Vol. 52, No. 12, 12.2005, p. 3755-3760.

Research output: Contribution to journalArticle

Cuzzocrea, Salvatore ; Mazzon, Emanuela ; Di Paola, Rosanna ; Genovese, Tiziana ; Muià, Carmelo ; Caputi, Achille P. ; Salvemini, Daniela. / Synergistic interaction between methotrexate and a superoxide dismutase mimetic : Pharmacologic and potential clinical significance. In: Arthritis and Rheumatism. 2005 ; Vol. 52, No. 12. pp. 3755-3760.
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abstract = "Objective. To investigate the effects of combination therapy with M40403 and methotrexate (MTX) on collagen-induced arthritis (CIA) in rats. Methods. 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). Results. 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. Conclusion. This study provides the first evidence that M40403, a potent superoxide dismutase mimetic, exerts a significant synergistic effect with MTX in rats with CIA.",
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