A New Peracetylated Oleuropein Derivative Ameliorates Joint Inflammation and Destruction in a Murine Collagen-Induced Arthritis Model via Activation of the Nrf-2/Ho-1 Antioxidant Pathway and Suppression of MAPKs and NF-κB Activation.

María Luisa Castejón,Marina Sánchez-Hidalgo,Tatiana Montoya,Alejandro González-Benjumea,María Ángeles Rosillo,Catalina Alarcón-De-La-Lastra,Jose G Fernández-Bolaños

doi:10.3390/nu13020311

Abstract

Oleuropein (OL), an olive tree secoiridoid and its peracetylated derivate (Per-OL) have exhibited several beneficial effects on LPS-stimulated macrophages and murine experimental systemic lupus erythematosus (SLE). This study was designed to evaluate dietary Per-OL in comparison with OL supplementation effects on collagen-induced arthritis (CIA) murine model. Three-weeks-old DBA-1/J male mice were fed from weaning with a standard commercial diet or experimental enriched-diets in 0.05 % (w/w) OL, 0.05% and 0.025% Per-OL. After six weeks of pre-treatment, arthritis was induced by bovine collagen type II by tail base injection (day 0) and on day 21, mice received a booster injection. Mice were sacrificed 42 days after the first immunization. Both Per-OL and OL diets significantly prevented histological damage and arthritic score development, although no statistically significant differences were observed between both compounds. Also, serum collagen oligomeric matrix protein (COMP), metalloprotease (MMP)-3 and pro-inflammatory cytokines levels were ameliorated in paws from secoiridoids fed animals. Mitogen-activated protein kinases (MAPK)s and nuclear transcription factor-kappa-B (NF-κB) activations were drastically down-regulated whereas nuclear factor E2-related factor 2 (Nrf2) and heme-oxygenase-1 (HO-1) protein expressions were up-regulated in those mice fed with OL and Per-OL diets. We conclude that both Per-OL and its parent compound, OL, supplements might provide a basis for developing a new dietary strategy for the prevention of rheumatoid arthritis.

Highlights

Rheumatoid arthritis (RA) is the most prevalent chronic, painful, and debilitating autoimmune disease in the world
0.05 and 0.025% experimental diets than in collagen-induced arthritis (CIA) control group from days 30 to 42. These results suggested that dietary OL and Per-OL could have a similar therapeutic behavior on going inflammatory arthritis
We described an increment of circulating matrix metalloproteinase-3 (MMP-3) levels in SD-CIA control group mice in comparison to SD-Naïve control group (** p < 0.01 vs. SD-Naïve control group) whereas these levels were significantly reduced after Per-OL and OL dietary treatments at all doses assayed

Summary

Introduction

Rheumatoid arthritis (RA) is the most prevalent chronic, painful, and debilitating autoimmune disease in the world. It characterized by chronic synovitis leading to the progressive destruction of joints accompanied by systemic inflammation and the production of autoantibodies. RA includes extraarticular manifestations, such as rheumatoid protuberances, pulmonary involvement or vasculitis and systemic comorbidities [1] affecting to the patient’s capacity to perform physical activities compared with the healthy population [2]. The pathogenesis of RA is multifactorial, substantial insights into RA pathophysiology suggest that various inflammatory pathways lead to an altered immune system and contribute to the joint damage during the disease. B-cells, T-cells and macrophages and even fibroblast-like synoviocytes play pivotal roles in RA pathogenesis [3]. Autoreactive B-cells produce rheumatoid factors (RFs) and/or

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