Grape seed proanthocyanidin extract (GSPE) attenuates collagen-induced arthritis
Introduction
Reactive oxygen species (ROS) such as the superoxide anion (O2−), hydrogen peroxide (H2O2), and the hydroxyl radical, are continuously generated during normal cell metabolism. ROS can act as a physiological defense system against microbial infection and are involved in maintaining normal cellular functions, including proliferation, apoptosis, and intracellular signal transduction [1]. However, excessive amounts of ROS can damage lipids, proteins, DNA, and the extracellular matrix [2]. Therefore, ROS must be scavenged by antioxidants. Enzymatic antioxidants include superoxide dismutase, glutathione peroxidase, catalase, and thioredoxin reductase. Nonenzymatic antioxidants include glutathione, vitamin A, vitamin C, and vitamin E [3]. Oxidative stress refers to the cellular state in which the production of ROS is elevated and/or the levels of antioxidants reduced. Oxidative stress is considered to be involved in the pathogenesis of atherosclerosis, cancer, neurodegenerative disorders, diabetes, ageing, and autoimmune rheumatological diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus, and systemic sclerosis [3].
RA is a chronic inflammatory autoimmune disease characterized by synovitis, bone destruction with pannus formation, and the degradation of the articular cartilage. The cause of RA is unknown, but several studies have suggested that oxidative stress is associated with the pathogenesis of RA. Epidemiological studies have demonstrated an inverse correlation between the dietary intake of antioxidants and the incidence of RA [4]. Inverse associations between serum antioxidant levels and the risk of developing RA have been reported [5]. The disease activity also correlates inversely with antioxidant levels and positively with the presence of oxidative stress in patients with RA [6], [7]. Increased oxidative enzyme activity has been demonstrated, together with reduced enzymatic and nonenzymatic antioxidant levels, in RA sera and synovial fluids [8]. Oxidative damage to proteins, lipids, DNA, cartilage, and extracellular collagen has been demonstrated in patients with RA [9]. Some drugs used to treat RA such as methotrexate, etancercept and infliximab are known to play essential roles as antioxidative agents [1]. Lipid peroxidation markers such as serum malondialdehyde and urine isoprostane are reported to be elevated in collagen-induced arthritis (CIA) compared with those in controls [10], [11]. The beneficial effects of antioxidants, including vitamin E, tempol, α-lipoic acid, N-acetylcysteine, the polyphenolic fraction of green tea, and (−)-epigallocatechin-3-gallate, have been demonstrated in mice with CIA [12], [13], [14], [15], [16], [17].
Grape seed extract is a natural plant constituent and contains lipids, proteins, carbohydrates, and polyphenols. Proanthocyanidins are the most abundant phenolic compounds in grape seeds, and are high-molecular-weight polymers comprised of dimers or trimers of (+)-catechin and (−)-epicatechin [18]. Grape seed proanthocyanidin extract (GSPE) has more powerful antioxidative activity than other well-known antioxidants, including vitamin C, vitamin E, and gallic acid [19]. GSPE has various biological functions such as antibacterial, antiviral, anti-inflammatory, antiallergic, and vasodilatory actions [20].
It has been suggested that GSPE is an effective therapy for oxidation-related diseases in animal models, including tumors, atherosclerosis, gastric ulcer, cataract, and diabetic retinopathy [21]. The beneficial effects of GSPE in reducing oxidized low-density lipoproteins and postprandial oxidative stress and improving chloasma have been demonstrated in human clinical trials [22], [23], [24]. However, little is known about the effects of GSPE on CIA and rheumatoid arthritis. To examine whether GSPE has therapeutic potentials in the treatment of RA, we examined the effects of GSPE on the severity of CIA in DBA/1 mice, using clinical, histological, and biochemical parameters. We found that GSPE treatment attenuates the severity of CIA in mice, reducing serum levels of type-II-collagen-specific IgG2a, inflammatory cytokine production, oxidative stress, bone destruction in vivo, and osteoclastogenesis in vitro.
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Animals
DBA/1J mice (SLC, Inc., Shizuoka, Japan), 6–8 weeks old, were housed in polycarbonate cages and fed with standard mouse chow (Ralston Purina, St Louis, MO, USA) and water ad libitum. All experimental procedures were examined and approved by the Animal Research Ethics Committee of the Catholic University of Korea.
Preparation of type II collagen
Bovine type II collagen was kindly provided by Professor Andrew Kang of the University of Tennessee. Type II collagen was extracted in its native form from fetal calf articular
Effects of GSPE treatment on arthritis scores
Arthritis developed about 3 weeks after the primary immunization of mice with type II collagen (Fig. 1). There was a significant dose-dependent reduction of the mean arthritis scores of the GSPE-treated mice compared with those of the control mice (Fig. 1).
Effects of GSPE treatment on histological findings
The effect of GSPE treatment on synovial inflammation was assessed by histological assessment. On day 60 after the primary immunization, the hind-paw joints of the mice were examined. In the CIA mice, the joints showed the infiltration of
Discussion
The polyphenols in GSPE have shown beneficial antioxidant effects on oxidative-stress-associated diseases. It has been suggested that oxidative stress plays an important role in the pathobiology of RA, and the beneficial therapeutic effects of antioxidants have been demonstrated in experimental models of RA [12], [13], [14], [15], [16], [17]. However, a recent systematic review of randomized clinical trials failed to show a clear effect of antioxidants such as vitamins A, C, and E and selenium,
Acknowledgements
This work was supported by a grant (R11-2002-098-05001-0) from the Korea Science & Engineering Foundation through the Rheumatism Research Center at the Catholic University of Korea and the Korea Science and Engineering Foundation (KOSEF) grant funded by the Korea government (MEST) (No. R01-2008-000-11737-0).
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These authors contributed equally to this work.