Elsevier

Pharmacological Reports

Volume 69, Issue 5, October 2017, Pages 1021-1029
Pharmacological Reports

Original article
Anti‐inflammatory and anti‐arthritic properties of naringenin via attenuation of NF‐κB and activation of the heme oxygenase ﴾HO﴿‐1/related factor 2 pathway

https://doi.org/10.1016/j.pharep.2017.03.020Get rights and content

Abstract

Background

Naringenin, a bioflavonoid present in various species of citrus fruit, tomatoes and grapes, has been shown to have various pharmacological effects. We evaluated the anti-arthritic potential of naringenin in formaldehyde-induced inflammation and complete Freund’s adjuvant (CFA)-induced arthritis.

Methods

For both evaluations, rats were divided into groups of six. Different doses of naringenin (5, 10 and 20 mg/kg) were used in the models. Body weight and the arthritic index were assessed. Biochemical and antioxidant parameters were determined. Naringenin dose-dependently reduced joint inflammation, decreasing the joint diameter and inflammatory cell infiltration.

Results

Naringenin-treated rats showed an improvement in the synovium redox status (down-regulation of malondialdehyde and glutathione and up-regulation of Catalase (CAT) and superoxide dismutase levels). Naringenin significantly reduced the level of the inflammatory marker TNF-α. Naringenin increased Nrf-2/HO-1 and reduced NF-κB mRNA levels in CFA-treated animal joints. Additionally, naringenin treatment decreased the expression of extracellular matrix degrading enzymes, such as matrix metalloproteinase (MMP-3 and MMP-9), in CFA-induced arthritic rats.

Conclusions

We conclude that naringenin exerts anti-arthritic effects by downregulating NF-κB and activating the Nrf-2/HO-1 pathway.

Introduction

Rheumatoid arthritis (RA) is a painful disease characterized by chronic inflammation and progression, affecting synovial joints and ultimately leading to joint destruction, including joint disability and deformity [1], [2]. RA has become more prevalent, perhaps as a result of an increasingly sedentary lifestyle. It is the most common autoimmune disease, occurring in ∼2% of the worldwide population. Reports have suggested that the epidemiological male-to-female ratio of RA is 1:3. It is also now more prevalent among younger populations as a result of changes in lifestyle and eating habits [3]. Several studies have shown that changes in diet, pollution, insecticides, an increased geriatric population, and other factors play significant roles in the pathogenesis of this painful and potentially crippling syndrome [4].

The pathogenesis of RA involves immune complexes, autoantibodies, T cell-independent proinflammatory cytokines, and T cell-mediated antigen-specific responses [5], [6]. Given this background, specific therapeutic treatments have been proposed to reduce joint destruction and synovial inflammation in RA. Indeed, treatment of arthritis can improve symptoms effectively, halting progression of the disease and curtailing suffering.

Because of the lack of available treatments to ‘cure’ RA, biologic treatments are used for management of the disease. Disease-modifying anti-rheumatic drugs such as hydroxychloroquine, azathioprine, azathioprine, methotrexate, sulphasalazine, and leflunomide, non-steroidal anti-inflammatory drugs (NSAIDs) such as etoricoxib, and corticosteroids such as prednisolone and methylprednisolone are widely used [7], [8]. These treatments act to decrease the levels of proinflammatory cytokines or cytokine receptors, which promote the joint destruction symptoms characteristic of RA. However, while these treatments are effective in attenuating the disease, they cause adverse effects such as immune suppression [7]. Due to the nature and progression, partial responses, and related side effects of the disease, there is a continuing need for new therapies for this disease [9].

Naringenin (4′,5,7-trihydroxyflavanone), a bioflavonoid present in tomatoes, citrus fruits, and grapes, has been shown to have various pharmacological effects [10], [11]. Naringenin exerted anti-inflammatory effects in an animal model of dextran sulfate sodium-induced colitis [12], [13]. Naringenin already confirm the inflammatory effect on the animal model. Due to anti-inflammatory effect of naringenin, we scrutinized the anti-inflammatory effect against chronic inflammation. Presently, there have been no reports regarding an anti-arthritic effect of naringenin or its possible mechanism of action.

Section snippets

Chemicals

Naringenin (95%) and indomethacin (99%) were purchased from Sigma Aldrich Chemical Company, USA. TNF-α, IL-6, and IL-1β ELISA kits were purchased from Bioscience, Netherlands. IL-6, TNF-R1, IL-1β, Nrf-2, HO-1, VEGF, IκBα, β‐actin, and NF-κB primary antibodies were purchased from Santa Cruz Biotechnology (Santa Cruz, CA, USA). All other chemical used were of analytical grade.

Animals

Wistar Swiss albino strain rats (130–180 g) were used. Rats were collected from the animal house of our institution and

Effects of naringenin on formaldehyde-induced inflammation

The acute anti-arthritic effects of naringenin were assessed against formaldehyde-induced acute inflammation. Assessments were made on day 10 after arthritis induction and at regular intervals; we evaluated the thickness of the paw in all rat groups. Formaldehyde-induced inflammation rats showed increased paw edema, which was significantly (p < 0.001) down-regulated by naringenin in a dose-dependent manner (Fig. 1).

Effects of naringenin on CFA-induced arthritis

The rats showed redness after CFA injection, which persisted for 14 days, and this

Discussion

‘Alternative’ medicines may have fewer side effects than those of some modern medications. Various medicinal plants have shown anti-arthritic effects, but researchers have continued to search for potential anti-arthritic drugs with maximum efficacy and fewer side effects. To advance anti-arthritic therapies, in the present investigation, we examined the anti-arthritic potential of naringenin in animal experimental models [16], [23]. The results suggest an anti-arthritic effect of naringenin, by

Funding

The current research was funded by the Department of Urology, Department of Orthopaedics, the Second People's Hospital of Liaocheng, China.

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