Oxidative Stress and the Use of Antioxidants for the Treatment of Rheumatoid Arthritis

Abstract

Oxidant stress as a result of increased production of reactive oxygen species (ROS) or a reduction in the body's endogenous antioxidant defense system is a hallmark of chronic inflammatory diseases including rheumatoid arthritis (RA). A primary source of ROS in RA is leukocytes (i.e. activated macrophages, neutrophils, mast cells and lymphocytes) that are recruited to, and that accumulate within, the synovium. ROS and reactive nitrogen species (RNS) can contribute to the pathogenesis of RA in a variety of ways including: induction of membrane oxidation and instability, irreversible damage to proteins and DNA, cartilage damage and induction of bone resorption. In addition, it has recently been appreciated that ROS/RNS can also modulate a variety of signaling events that control gene expression and effect cellular processes that participate in chronic inflammation. These include effects on vascular tone, cell growth and proliferation and induction of pro-inflammatory genes. Consistent with a role for oxidant stress in the pathogenesis of RA, a number of preclinical and clinical studies have correlated increases in markers of oxidative stress and lower levels of the body's natural antioxidants with disease severity. Accordingly, a variety of methods aimed at reducing ROS production, scavenging ROS or restoring the antioxidant balance have been tested with some success in experimental models of RA and in clinical trials. Although considerable data supports the notion that antioxidant-based drugs could prove beneficial in the treatment of RA, very few have been evaluated clinically and to date none have demonstrated clinical proof-ofconcept in Phase II clinical studies.

Reduction of oxidative stress in adjuvant arthritis. Comparison of efficacy of two pyridoindoles: stobadine dipalmitate and SMe1.2HCl.

“…Several clinical studies as well as preclinical animal models of RA have documented an imbalance in the body's reduction/oxidation homeostasis to a more pro-oxidative environment, suggesting that therapies which restore the redox balance may have beneficial effects on the disease process. The role of ROS in the etiology of RA is supported by numerous studies documenting that not only the damaging effects of ROS but also the role that ROS play in regulating various inflammatory processes contributes to the pathogenesis of the disease (Kunsch et al, 2005). The net effect of redox signaling are highly specific changes in gene expression and in the cellular phenotype.…”

Modern Pharmacological Approaches to Therapies: Substances Tested in Animal Models of Rheumatoid Arthritis

“…Granulocytes and autoreactive CD41 which restore the redox balance may have beneficial effects on the disease process. The role of reactive oxygen species (ROS) in the etiology of RA is supported by numerous studies documenting that not only the damaging effects of ROS but also the role that ROS play in regulating various inflammatory processes contributes to the pathogenesis of the disease (Kunsch et al, 2005). The net effect of redox signaling is highly specific changes in gene expression and in the cellular phenotype.…”

Peroxynitrite and 4-Hydroxynonenal Inactivate Breast Cancer Resistance Protein/ABCG2

“…Oxidative stress is a frequent complication of various disease conditions such as Alzheimer and Parkinson's diseases [1, 2], atherosclerosis [3], HIV [4], preeclampsia [5], rheumatoid arthritis [6], and diabetes [7] including gestational diabetes [8]. Different molecules associated with oxidative stress are involved in the development of pathogenesis; however peroxynitrite (PN) and 4-hydroxynonenal (4HNE) are the most studied.…”