A REVIEW OF FREE RADICALS AND RHEUMATOID ARTHRITIS

About Authors:
Purbajit Chetia*, Manash Pratim Pathak, Prerona Das
Deptt. of Pharmacology,
Himalayan Pharmacy Institute, Majhitar,
Rangpo, E- Sikkim(737132)
*purbasiv@yahoo.com

ABSTRACT:
A free radical is an atom or group of atoms that contains at least one unpaired electron and can easily bond with another atom or molecule, causing a chemical reaction. Free radical is essential for body’s normal physiological functions. But when produced in excess quantities it can causes damage to the cells of the body. Human body generates pro-oxidants in the form of ROS and RNS which are effectively kept in check by the various levels of antioxidant defense. However, when it gets exposed to adverse physicochemical, environmental or pathological agents this delicately maintained balance is shifted in favor of pro-oxidants resulting in ‘oxidative stresses’. It has been implicated in the etiology of several human diseases including Rheumatoid Arthritis (RA) and in the process of ageing.At high concentrations, ROS can be important mediators of damage to cell structures, nucleic acids, lipids and proteins in case of the patients those who are suffering from RA. The hydroxyl radical is known to react with all components of the DNA molecule, damaging both the purine and pyrimidine bases and also the deoxyribose backbone. Rheumatoid arthritis is an autoimmune disease that causes chronic inflammation of the joints and tissue around the joints with infiltration of macrophages and activated T cells. The pathogenesis of this disease is linked predominantly with the formation of free radicals at the site of inflammation. The review is focusing the evidences concerning the involvement of free radicals in Rheumatoid Arthritis and their relationship to specific pathophysiological events.

Reference Id: PHARMATUTOR-ART-1336

INTRODUCTION:
Free radicals can be defined as molecules or molecular fragments containing one or more unpaired electrons in atomic or molecular orbitals and is capable of exciting independently ¹. Generally free radicals attack the nearest stable molecule by stealing it’s electron. The attack molecule then loses its electron and becomes a free radical itself, beginning a chain reaction cascade resulting in damage to the living cells ². Free radicals can be formed by hemolytic bond fission or by electron transfer reactions. In general such process proceed either through the absorption of radiation, redox reaction, oxidative phosphorylation in mitochondria, activation of phagocytic cells, biotransformation of exogenous and endogenous compounds in endoplasmic reticulum etc. The precursors of free radical include a variety of xenobiotics like photochemicals, pollutants, cigarette smoking, chemicals drugs, heavy metals and the constituents of many food stuff as well as endogenous compounds that can be converted to reactive radical spesis ³. Some common free radicals are such as superoxide anion radical (O₂ •−), hydroxyl radical, (•OH), Peroxyl radical (HOO•),Nitric oxide (NO•) etc. The present paper concentrates on the reviewing of the evidences concerning the involvement of free radicals in Rheumatoid Arthritis and their relationship to specific pathophysiological events.

Superoxide anion:
Molecular oxygen (dioxygen) which has a unique electronic configuration and is itself a radical forms the superoxide anion radical (O₂ •−) by adding of one electron to dioxygen ⁴. The mitochondria of a cell are mainly responsible for the production of superoxide radical. The mitochondrial electron transport chain is the main source of ATP in the mammalian cell and thus is essential for life. During energy transduction, a small number of electrons “leak” to oxygen prematurely, forming the oxygen free radical superoxide, which has been implicated in the pathophysiology of a variety of diseases ⁵.

Hydroxyl radical:
The hydroxyl radical, •OH, is the neutral form of the hydroxide ion. The hydroxyl radical has a high reactivity, making it a very dangerous radical with a very short in vivo half-life ⁶.Thus when produced in vivo •OH reacts close to its site of formation. Under stress conditions, an excess of superoxide releases “free iron” from iron-containing molecules that can participate in the Fenton reaction, generating highly reactive hydroxyl radical .Thus under stress conditions, (O₂•−) facilitates •OH production from H₂O₂ by making Fe2+ available for the Fenton reaction⁷.

Peroxyl radical:
HOO•is the simplest peroxyl radical which is the protonated form of superoxide (O₂ •−) and is usually termed either hydroperoxyl radical or perhydroxyl radical that initiates fatty acid peroxidation ⁸. Peroxisomes are major sites of oxygen consumption in the cell and participate in several metabolic functions that use oxygen. It maintains a delicate balance with respect to the relative concentrations or activities of the enzyme like catalase to ensure no net production of ROS. When peroxisomes are damaged and their H₂O₂ consuming enzymes downregulated, H₂O₂ releases into the cytosol which is significantly contributing to oxidative stress ⁹.

Nitric oxide:
NO• is a small molecule that contains one unpaired electron. Itis generated in biological tissues by specific nitric oxide synthases (NOSs), which metabolise arginine to citrulline with the formation of NO• via a five electron oxidative reaction¹⁰. Nitric oxide (NO•) is an abundant reactive radical that acts as an important oxidative biological signalling molecule in a large variety of diverse physiological processes, including neurotransmission, blood pressure regulation, defence mechanisms, smooth muscle relaxation and immune regulation. In the extracellular milieu, NO• reacts with oxygen and water to form nitrate and nitrite anions. Overproduction of reactive nitrogen species is called nitrosative stress ¹¹.This may occur when the generation of reactive nitrogen species in a system exceeds the system’s ability to neutralize and eliminate them. Nitrosative stress may lead to nitrosylation reactions that can alter the structure of proteins and so inhibit their normal function. Cells of the immune system produce both the superoxide anion and nitric oxide during the oxidative burst triggered during inflammatory processes. Under these conditions, nitric oxide and the superoxide anion may react together to produce significant amounts of a much more oxidatively active molecule, peroxynitrite anion (ONOO−), which is a potent oxidising agent that can cause DNA fragmentation and lipid oxidation ¹².

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ROLE OF FREE RADICALS IN RHEUMATOID ARTHRITIS:
Rheumatoid arthritis (RA) is a chronic and systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium (synovitis) secondary to hyperplasia of synovial cells, excess synovial fluid, and the development of pannus in the synovium ¹³. The pathogenesis of this disease is linked predominantly with the formation of free radicals at the site of inflammation. Oxidative injury and inflammatory status in various rheumatic diseases was confirmed by increased levels of isoprostanes and prostaglandins in serum and synovial fluid compare to controls ¹⁴. RA typically affects hands and feet, although any joint in the body may be affected such as wrists, knees, hips and shoulders. Over time, joint destruction can occur resulting in permanent damage, bone destruction and deformity ¹⁵. It is associated with an increase in various proinflammatory factors that include cytokines (IL-1 β , IL-6, tumour necrosis factor alpha TNF- α), prostaglandins, reactive oxygen species (ROS) and nitric oxide (NO) at sites of inflammation, coupled with very low concentrations of superoxide dismutase (SOD) in the synovial fluid ¹⁶.

Rheumatoid arthritis (RA) is a leading cause of disability that often reduces patients’ quality of life and impairs their ability to work ¹⁷. A number of cellular and molecular components controlled the development of inflammatory reaction in RA. Nitric oxide (NO) is a short-lived signaling molecule that plays an important role in a variety of physiologic functions, including the regulation of blood vessel tone, in?ammation, mitochondrial functions and apoptosis ¹⁸. It is well established now that free radicals/reactive oxygen species play an important role in inflammation. The most important reactive oxygen species (ROS) implicated in inflammatory injuries to tissues are the superoxide radical (O₂ •−), hydrogen peroxide (H₂O₂), hydroxyl radical (•OH), and hypochlorous acid (HOCI). ROS may arise also in the inflamed joint by several mechanisms. Oxidants can be produced by activated macrophages in the synovial membrane, by chondrocytes, and by activated neutrophils in the synovial cavity. It has also been proposed that movement of an inflamed joint generates sufficient pressure to cause transient ischaemia of the superficial membrane. In health the synovial cavity exhibits negative pressure, and when the joint is exercised, vascular patency is maintained, allowing for nutrition of the a vascular cartilage. In RA, the cavity pressure is raised and upon movement this pressure exceeds the capillary perfusion pressure, causing collapse of the blood vessels. This leads to the production of multiple episodes of "hypoxicreperfusion injury", generating reactive oxygen species ¹⁹.

H₂O₂cannot damage most biological macromolecules directly but In the presence of "catalytic" iron ions, (O₂ •−) and H₂O₂ may be converted to •OHby the Haber-Weiss reaction. Again the interaction of NO•and (O₂ •−) forms the cytotoxic product peroxynitrite (ONOO-) which is most dangerous free radical in the body causing high damage to the synovium of the joints ²⁰. (•OH)may react at a diffusion controlled rate with almost all molecules in living cells. Oxidation of proteins, lipids, DNA, uric acid, polysaccharides has been shown to be increased in rheumatoid arthritis patients. In addition, H₂O₂ dependent inactivation of enzymes in cartilage may lead to inhibition of proteoglycan synthesis, so contributing to cartilage destruction in rheumatoid arthritis by interfering with the repair of proteolytic and oxidative damage ²¹. Nitric oxide (NO) has a role in the regulation of vascular tone, contributing to cardinal signs of inflammation². Several studies have evidenced for increased endogenous NO synthesis in patients with RA, which suggest that there is an overproduction of NO that may be important in the pathogenesis of RA. The inflamed joint in RA is the predominant source of NO ²². Several investigators found correlations between serum nitrite concentration and RA disease activity or radiological progression. It has been shown recently that T cells from RA patients produce more than 2.5 times more NO than healthy donor T cells ²³.

Although free radicals seem to be a considerable factor of the disease like rheumatoid arthritis, the human body has several mechanisms to counteract damage by free radicals and other reactive oxygen species. The enzyme systems, including superoxide dismutases, glutathione peroxidases and catalase and antioxidants, including glutathione, ubiquinol and uric acid which decrease concentrations of the most harmful oxidants in the tissues is one of the most important part of defense. Several essential minerals including selenium, copper, manganese and zinc are necessary for the formation or activity of these enzymes. Some antioxidants are produced during normal metabolism in the body. Other lighter antioxidants are found in the diet²⁴. Vitamin E, vitamin C and the carotenoids are the best antioxidants identified in recent years. Many other non-nutrient food substances, generally phenolic or polyphenolic compounds and flavinoids show antioxidant properties and, thus, may be important for the preventive measure for the disease like Rheumatoid Arthritis.

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