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In vivo dual inhibition of cyclooxygenase and lipoxygenase by ML-3000 reduces the progression of experimental osteoarthritis: Suppression of collagenase 1 and interleukin-1β synthesis

Abstract : Objective. To study the therapeutic effectiveness of ML-3000, a new antiinflammatory drug that has balanced dual inhibitory activity against 5-lipoxygenase and cyclooxygenase, on the development of lesions in the experimental osteoarthritis (OA) dog model, and to determine the action of ML-3000 on the synthesis of collagenase 1 in cartilage and interleukin-1 (IL-1) in synovial membrane. Methods. The anterior cruciate ligament of the right stifle joint of 21 mongrel dogs was sectioned with a stab wound. Dogs were divided into 3 groups: group 1 (n 7) received placebo; groups 2 (n 7) and 3 (n 7) were treated with therapeutic dosages of oral ML-3000 at 2.5 mg/kg/day and 5 mg/kg/day, respectively. The dogs began receiving medication the day after surgery and were killed 8 weeks later. The size and grade of cartilage erosions on both the condyles and plateaus were evaluated, and the severity of the cartilage lesions and synovial inflammation was examined histologically. Levels of collagenase 1 in cartilage and IL-1 in the synovial membrane were measured by immunohisto-chemistry. In addition, levels of prostaglandin E 2 (PGE 2) in the synovial fluid and leukotriene B 4 (LTB 4) in cultured synovial membrane explants were determined using specific enzyme immunoassays. Results. Serum levels of ML-3000 in treated dogs were within the therapeutic range. ML-3000 significantly decreased the size and grade of the cartilage lesions in tibials and plateaus, compared with placebo. At the histo-logic level, the severity of cartilage lesions was also decreased in the ML-3000–treated dogs versus the placebo-treated dogs in both the condyles and the plateaus. All 3 OA groups exhibited a notable and similar level of synovial inflammation. ML-3000 significantly decreased the level of PGE 2 in synovial fluid and LTB 4 production by synovium. It also markedly reduced the levels of collagenase 1 in cartilage and IL-1 in synovial membrane. Conclusion. ML-3000 significantly reduced the development of lesions in experimental dog OA. The drug acts by reducing the synthesis of the inflammation mediators PGE 2 and LTB 4 and catabolic factors such as collagenase 1 and IL-1, which are known to play an important role in the pathophysiology of OA lesions. The effect of the drug on catabolic factors could possibly be related to its inhibitory action on LTB 4 synthesis.
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Submitted on : Friday, February 9, 2018 - 5:20:23 PM
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Dragan Jovanovic, Julio Fernandes, Johanne Pelletier, François-Cyril Jolicoeur, Pascal Reboul, et al.. In vivo dual inhibition of cyclooxygenase and lipoxygenase by ML-3000 reduces the progression of experimental osteoarthritis: Suppression of collagenase 1 and interleukin-1β synthesis. Arthritis and Rheumatism, Wiley, 2001, 44 (10), pp.2320-2330. ⟨10.1002/1529-0131(200110)44:10<2320::AID-ART394>3.0.CO;2-P⟩. ⟨hal-01705269⟩

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