N‐feruloylserotonin in preventive combination therapy with methotrexate reduced inflammation in adjuvant arthritis

Abstract

Many of disease-modifying anti-rheumatic drugs often have side effects at high doses and/or during long-term administration. Increased efficacy without increased toxicity is expected for combination therapy of rheumatoid arthritis (RA). The aim of the study was to examine the effect of N-feruloylserotonin (N-f-5HT) and methotrexate (MTX) in monotherapy and in combination therapy on disease progression and inflammation in arthritic rats. Adjuvant arthritis was induced by intradermal injection of Mycobacterium butyricum in incomplete Freund's adjuvant in Lewis rats. The experiment included healthy animals, arthritic animals without any drug administration, arthritic animals with administration of N-f-5HT in the oral daily dose of 15 mg/kg b.w., arthritic animals with administration of MTX in the oral dose of 0.3 mg/kg b.w. twice a week and arthritic animals treated with the combination of N-f-5HT and MTX. N-f-5HT in monotherapy reduced only activation of NF-κB and did not have any significant effect on other parameters monitored. Low-dose treatment of MTX decreased the level of IL-1β and MCP-1 on day 14 and activation of NF-κB in liver without significant effect on other parameters. N-f-5HT and MTX combination showed both the anti-arthritic (hind paw volume and arthritic score) and anti-inflammatory effect (plasmatic levels of IL-1β, IL-17, MCP-1, CRP, and activation of NF-κB in liver). In combination with MTX, N-f-5HT markedly potentiated the therapeutic effect of MTX low dose, which resulted in significant improvement of all parameters measured. The findings showed that the combination therapy simultaneously decreased multiple markers of inflammation, a result crucial for future therapy of RA.

Synergistic enhancement and hepatoprotective effect of combination of total phenolic extracts of Citrus aurantium L. and methotrexate for treatment of rheumatoid arthritis

“…Previous studies suggest that production of proinflammatory cytokines such as TNF‐α, IL‐6, and IL‐β plays an important role in inflammatory responses (Kuncirova et al, ). To further investigate the underlying antiinflammatory mechanisms induced by the combination of MTX and TPE‐CA, we measured content of inflammatory cytokines such as TNF‐α, IL‐6, IL‐1β, and CRP as a systematic inflammatory marker (Christian Gytz et al, ) involved in RA rats.…”

“…After combination treatment with MTX and TPE‐CA, the number of PLT in CIA rats was markedly decreased. Chronic inflammation‐stimulated bone destruction is a characteristic pathological feature of RA (Kuncirova et al, ). Micro‐CT images showed that bone parameters, including BV/TV and Tb.…”

“…Rheumatoid arthritis (RA) is a chronic and systemic inflammatory disease characterized by joint destruction, bone damage, disability, and premature death, resulting in a considerable economic burden on patients and society (Hao et al, ). Although the etiology of RA has not been completely elucidated, it is known that the inflammatory region is characterized by high infiltration of chemokines and inflammatory cytokines, which are responsible for the damage of the bones and joints (Kuncirova et al, ). Continuous migration of leukocytes and cytokines can lead to formation of blood vessels in the synovial tissue.…”

“…MTX is a cell cycle specific agent and can only target a limited number of proteins. As combined therapy has shown success in treating leukemia, combination regimen may be an effective approach and can lead to better outcomes than with monotherapy (Kuncirova et al, ). Thus, MTX‐based combination therapy could be an alternative strategy to improve the low response of MTX in RA treatment.…”

Immunohistochemical determination of the extracellular matrix modulation in a rat model of choline‐deprived myocardium: the effects of carnitine

“…Matrix metalloproteinases (MMPs) are a family of latent zinc‐ and calcium‐dependent proteolytic enzymes that mediate changes in the extracellular matrix (ECM) participating in many physiological processes such as morphogenesis, development and apoptosis . Moreover, their role is crucial in various pathological processes as well, involved in the pathogenesis of different diseases such as chronic obstructive pulmonary disease , cancer , liver cirrhosis and arthritis , while they are also engaged in cardiovascular diseases including arterial hypertension , pulmonary hypertension , coronary artery disease , stroke and cardiac hypertrophy . They are gaining increasing clinical interest as important players in vascular remodeling, atherogenesis and thrombosis .…”