Ferulaldehyde Improves the Effect of Methotrexate in Experimental Arthritis.

Lukáš Slovák,Katarína Bauerová,František Bilka,Danica Mihalová,Jaroslav Tóth,Karol Švík,Ľudmila Pašková,Szilvia Czigle

doi:10.3390/molecules22111911

Abstract

Methotrexate (MTX) is still the gold standard for treatment of rheumatoid arthritis (RA). The therapeutic efficacy of low-dose of MTX can be increased by its combination with a natural substance, ferulaldehyde (FRA). The aim of this study was to evaluate the effect FRA and MTX administered alone or in combination in adjuvant arthritis. The disease was induced to Lewis male rats by intradermal injection, which contains a suspension of heat-inactivated Mycobacterium butyricum in incomplete Freund’s adjuvant. The experiment of 28 days included: healthy animals, arthritic animals, arthritic animals with administration of FRA at the oral daily dose of 15 mg/kg, arthritic animals with administration of MTX at the oral dose of 0.3 mg/kg twice a week, and arthritic animals administered with FRA and MTX. FRA in monotherapy decreased significantly only the level of interleukin-1β (IL-1β) and matrix metalloproteinase-9 in plasma. Combination of FRA and low-dose MTX was more effective than MTX alone when comparing body weight, hind paw volume, arthritic score, plasmatic levels of IL-1β, activity of γ-glutamyl transferase, and relative mRNA expression of IL-1β in the spleen. Therefore, the combination treatment was the most effective. The obtained results are interesting for future possible innovative therapy of patients with RA.

Highlights

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease
The change of body weight (CBW) of arthritic animals showed a decrease during the experiment in comparison to the control group on all days monitored
Administration of FRA to arthritic animals during all 28 days induced no significant modification of Change of body weight (CBW) compared to group Adjuvant arthritis (AA)

Summary

Introduction

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease. A high-risk genetic background, in combination with epigenetic marks and environmental exposures, leads to a cascade of events inducing synovitis with consequent destructive arthritis, affecting a variety of extra-articular organs [1,2,3]. Adjuvant arthritis (AA) exhibits clinical and pathological features similar to human RA. This model may not reproduce all the features of arthritis in humans, it can help to further the understanding of normal inflammatory and immune responses during RA [5]. The treatment of RA is still unsatisfactory, but several powerful disease-modifying antirheumatic drugs have become available, such as methotrexate (MTX). Even in the current era of biological targeted therapies, MTX remains the initial preferred antirheumatic drug as the gold standard for the treatment of RA. The combination of its perceived efficacy, acceptable safety profile, and low cost, as well as decades of clinical experience, makes MTX the cornerstone of treatment for RA and the anchor drug in combination with various biological agents [6]. If MTX is effective, Molecules 2017, 22, 1911; doi:10.3390/molecules22111911 www.mdpi.com/journal/molecules

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