N-(2-hydroxy phenyl) acetamide inhibits inflammation-related cytokines and ROS in adjuvant-induced arthritic (AIA) rats
Introduction
Rheumatoid arthritis (RA) is the most common chronic inflammatory pain condition and leading cause of activity limitations in mid and late life [1], [2], [3], [4]. RA is characterized by severe pain, swelling and destruction of cartilage and bone that leads to impaired joint function [5]. It is a systemic autoimmune disease involving mainly the peripheral synovial joints and causing chronic inflammation and profound tissue destruction in affected patients. The autoimmune characteristic of RA is best supported by the presence of circulating autoantibodies (autoAbs) against immunoglobulins (rheumatoid factor), citrullinated proteins and other endogenous proteins [6], [7], [8], which may become detectable in serum years before the development of joint symptoms [9]. The systemic production of autoAbs indicates that autoreactive T cells that provide help to B cells for Ab secretion are located in the secondary lymphoid organs, and are, therefore, indirectly involved in disease pathogenesis. However, studies suggest that T cells recruited in the joints of RA patients may be directly involved in the initiation and propagation of arthritis [6], [9]. Several pro-inflammatory cytokines, such as TNF-α and IL-1β have been reported to play an important role in the pathogenesis of rheumatoid arthritis [10], [11].
It has also been reported that free radicals including nitric oxide, peroxide, singlet oxygen and hypochlorous acid at the site of inflammation are involved in the pathogenesis of RA [12]. These free radicals are able to destroy membrane lipids, proteins, DNA and cartilage [13]. Reactive oxygen (ROS) and nitrogen species are products of normal cellular metabolism however their excessive formation is a downstream consequence of tissue injury that leads to many pathological conditions such as cancer, cardiovascular diseases, atherosclerosis and rheumatoid arthritis [14]. Normally the cells are protected against these species by a series of enzymatic and non-enzymatic defense mechanisms including superoxide dismutase, glutathione peroxidase, catalase, glutathione and ascorbate [15], [16], [17], [18]. The overproduction of ROS and reduced levels of superoxide dismutase and glutathione in RA patients exposes them to oxidative stress-induced tissue destruction [19], [20], [21], [22], [23]. Superoxide radical and hydrogen peroxide not only induce the production of interleukins and TNF-α from T cells but also stimulate the endothelial cells which then influence the production of growth factor, inflammatory cytokines and adhesive molecules on the immune cells thereby aggravating the tissue destruction and inflammation [24], [25], [26], [27], [28], [29], [30].
Although there is no cure for rheumatoid arthritis, there are treatments available which may effectively alleviate the symptoms and improve the quality of life. The non-steroidal anti-inflammatory drugs and glucocorticoids are largely used for treatment of rheumatoid arthritis in spite of their systemic, gastric and renal toxicities [31], [32], [33], [34], [35], [36], [37]. These currently available analgesics and anti-inflammatory drugs are clearly not adequate therapy due to the adverse effects associated with their extended use in chronic conditions. Moreover, NSAIDs have no effect on the basic disease process and do not protect against tissue or joint injury [38]. Furthermore, it has been shown that NSAID treatment enhances joint destruction in arthritis [39] and inhibits glycosaminoglycans synthesis by articular chondrocytes [40]. Acetaminophen (4-hydroxyacetanilide), a popular analgesic and anti-pyretic, lacks some of the side effects of aspirin and has been used as the largest aspirin substitute. However, it is associated with hepatotoxicity and nephrotoxicity due to metabolic conversion of the drug into a reactive intermediate by the cytochrome P450 dependent mixed function oxidase system [41], [42], [43].
Keeping in mind the problems associated with the use of glucocorticoids and NSAIDs, there is always a need to come up with new therapy which could give symptomatic relief of pain and inflammation associated with arthritis and also has minimal side effects over extended use. Since N-(2-hydroxy phenyl) acetamide (NA-2), a derivative of salicylic acid has shown potent anti-inflammatory activity in our earlier studies [44], therefore, in the present study we have focused on evaluating its possible anti-arthritic activity. 2-Acetamidophenol is a commercially available compound and is also known as, O-hydroxyacetanilide, 2-hydroxyacetamide, O-acetaminophenol and 2-acetylaminophenol. To our knowledge not much work has been done on this compound, however, Saeed and Saeed in 2005 reported that it is a less toxic compound compared to paracetamol or aspirin and can be use as an anti-inflammatory and anti-platelet aggregating agent [45]. Even after extensive literature search we were unable to find any reported toxicity associated with NA-2.
Based on our preliminary results, in the present study we have explored not only the potency of NA-2 as an anti-arthritic agent but also evaluated its effects on the arthritic mediators including inflammatory cytokines TNF-α and IL-1ß, nitric oxide, peroxide and glutathione.
Section snippets
Animals
Female Sprague Dawley (SD) rats weighing 215–230 g were used in this study. The animals were housed at 21 ± 2 °C and on a 12-h light/dark cycle with free access to standard laboratory rat food pellets and water. The ethical guidelines of the International Association for the Study of Pain in conscious animals were followed [46]. Rats were randomly distributed into each treatment group of twelve animals. The group size was determined as the minimum number of rats for valid statistical analysis and
Effects of NA-2 on clinical signs of adjuvant-induced arthritis
From day 10 onwards, the arthritic control group began to show evidence of clinical inflammation in one or both hind paws, however, the paw volume was significantly different from day 14 onward (p < 0.012) compared to the normal control group (Fig. 1). The first manifestation of disease was erythema of one or more ankle joints, followed by involvement of the metatarsal and interphalangeal joints. Likewise, on day 18 onward a non-significant increase was also observed within arthritic groups
Discussion
Adjuvant-induced arthritis is a widely used arthritic model for testing and developing anti-arthritic and anti-inflammatory agents. However, its extensive use is sometimes restricted due to the variations in the incidence and severity of the disease, and the narrow number of susceptible rat strains available. In the present study, we have used SD rats which are considered to be a moderate-responder strain to AIA, and demonstrated, that following intradermal inoculation (at the base of the tail)
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