Anti-inflammatory and analgesic effects of atorvastatin in a rat model of adjuvant-induced arthritis

Abstract

Statins exert favorable effects on lipoprotein metabolism but may also possess anti-inflammatory effects. Here, we explored the effects of atorvastatin in a model of adjuvant-induced arthritis in rat. Oral treatment with atorvastatin (1–10 mg/kg) from days 10 to 15 after arthritis induction caused inhibition of the increase in paw volume. Maximal inhibition occurred at a dose of 10 mg/kg. At this dose, atorvastatin markedly ameliorated the histopathological findings of joints obtained from day 16 of arthritic animals. This was mirrored by an effective blockade of neutrophil influx, as assessed by the tissue myeloperoxidase levels. The concentrations of the cytokines interleukin-1β, interleukin-6 and tumor necrosis factor-α and the chemokines CCL5 and CCL2 were significantly decreased in arthritic rats treated with atorvastatin. In contrast, the levels of interleukin-10 were enhanced by the drug treatment. The drug also prevented the hypernociception observed in the inflamed joints. These data clearly illustrate the therapeutic potential of a statin-sensitive pathway in inflammatory arthritis.

Introduction

Statins represent a well-established class of drugs that effectively lower serum cholesterol levels and are widely prescribed for the treatment of hypercholesterolemia. Statins competitively inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, reducing the availability of l-mevalonate and cholesterol biosynthesis (Kwak et al., 2003, Kwak et al., 2000, Weitz-Schimidt, 2002). In addition to its anti-hypercholesterolemic effects, several reports have now described the ability of statins to interfere with secretion of cytokines and with leukocyte function and migration. For example, statins decrease the secretion of pro-inflammatory cytokines IL-6 (interleukin-6) and IL-8 (interleukin-8) from macrophages and inhibit the release of the chemokine CCL2/MCP-1 (macrophage chemotactic protein-1) from these cells (Chen et al., 2000, Zelvyte et al., 2002). The molecular mechanisms subserving such anti-inflammatory and/or immunomodulatory activities remain unclear.

Recent studies have focused on the ability of statins to modulate chronic inflammatory diseases, such as multiple sclerosis (Youssef et al., 2002). In animal models of the latter condition, atorvastatin prevented or reverted chronic and relapsing paralysis and inhibited the secretion of cytokines IL-2, IL-12, TNF-α (tumor necrosis factor-α), and IFN-γ (interferon type I). Rheumatoid arthritis is another common chronic inflammatory disorder that is characterized by joint inflammation with concomitant destruction of cartilage and bone (Swell and Trentham, 1993). Several pro-inflammatory cytokines, such TNF-α and IL-1β, and chemokines, such as CCL2 and CCL5, are reported to play a role in the pathogenesis of rheumatoid arthritis (Maini and Taylor, 2000, Feldmann et al., 2001, Kaplan et al., 2002). Although there are reasonably good drugs used in the symptomatic relief of arthritis, such as non-steroidal anti-inflammatory drugs, current treatment is still not satisfactory to modify fundamental pathologic processes responsible for the chronic inflammation (Lane, 1997). Cytokine-based therapies have been used for the treatment of rheumatoid arthritis and found to be useful in preventing progression of chronic arthritis in groups of patients. However, the latter therapies are based on the use of exogenous proteins (such as antibodies), which are costly and with the inherent possibility of an immune response against the exogenous protein and need for systemic injection.

Simvastatin treatment has been reported to improve the course of collagen-induced arthritis (CIA) in mice (Leung et al., 2003). Simvastatin administered intraperitoneally at a dose of 40 mg/kg was shown to suppress arthritis whereas lower doses of the drug (10 or 20 mg/kg) had no significant effect. Consistently, a controlled clinical study showed for the first time a potential effect of atorvastatin treatment on human rheumatoid arthritis (McCarey et al., 2004). In the present study, we have used a model of adjuvant-induced arthritis in rats to examine the effects of the treatment with atorvastatin on disease development. The drug was administered after the first signs of disease development (day 10 after the injection of adjuvant) and the following parameters were examined: increase in paw volume, nociception, pathology, neutrophil migration, and local production of pro-inflammatory cytokines and chemokines. The choice of atorvastatin was based on previous studies demonstrating the effectiveness of this drug on other models of chronic inflammation in rats (Youssef et al., 2002) and in preliminary data demonstrating effectiveness in humans (McCarey et al., 2004).