Introduction

The term "free radicals" designates a family of compounds characterized by great reactivity due to the impaired electron in the outer orbital. To this group belong reactive oxygen species (ROS), such as superoxide anion, hydroxyl radical and hydrogen peroxide, as well as reactive nitrogen species (RNS) which include nitric oxide and peroxynitrite. Although structurally different, free radicals share similar mechanisms to harm body's cells and tissues through damage on proteins, DNA and lipids [1]. The alterations of membrane functions occurring as a consequence of phospholipid modifications represent a relevant, radical species-dependent injury, either when considering the organism as a whole, or a specific integrated function, such as the immune response [2]. The potential therapeutic applications of antioxidants in free radical-related diseases led to the hypothesis of their use to slow down or reverse, for example, symptoms associated with with neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), or spongiform encephalopathies. Such effect could occur through a block of proinflammatory cytokines action and the resulting oxidative damage [3-7]. However, several clinical studies demonstrated that not only malnutrition, but also the excess of certain nutrients (e.g. iron, alpha-tocopherol, beta-carotene, ascorbic acid) may set into motion oxidation phenomena and, therefore, cell injury [8,9]. Thus, it is of relevance that prior to considering introducing antioxidant therapy into mainstream medicine, significant advances in basic cell biology, pharmacology and clinical bioanalysis will be required.

Oxidative Stress

The body is normally under a dynamic equilibrium between free radical generation and quenching. The physiological defense systems to counteract free radicals encompass endogenous enzyme systems, such as catalase, glutathione reductase and superoxide dismutase, as well as glutathione, urate and coenzyme Q, or exogenous factors (β-carotene, vitamin C, vitamin E and selenium) [10]. All these molecules have an antioxidant effect due to their ability to transform ROS into stable and harmless compounds or by scavenging both ROS and RNS with a redox-based mechanism [10]. Very recently, a main role in the fight against oxidative stress has been assumed by enzymes such as heme oxygenase (HO) and biliverdin reductase (BVR). Heme oxygenase is a microsomal enzyme which metabolizes heme into ferrous iron, carbon monoxide and biliverdin (BV); the latter is then reduced by BVR into bilirubin (BR), a molecule endowed with strong antioxidant and antinitrosative activities [11-14]. Interestingly, all these protective factors act in a concerted way, enhancing the antioxidant defense system of the cell. When the balance between ROS/RNS and antioxidants turns in favor of the former, oxidative/nitrosative stress occurs. Although oxidative stress is associated with most diseases, routine assay methods are not nowadays available in the clinical practice. A strategy widely used to determine oxidative stress is measurement of malonyldialdehyde, F2-isoprostanes, or 8-hydroxydesoxyguanosine. Actually, these molecules are regarded as the most reliable markers available [15]. A classic example of an oxidation product apparently leading to disease, is oxidized cholesterol in low-density lipoprotein (LDL), which displays a higher atherogenic potential than native LDL, and mainly involved in the pathogenesis of atherosclerosis and coronary heart disease (CHD) [16].