ANTIOXIDANTS & FREE-RADICAL SCAVENGERS are grouped here. Antioxidants are used both to prolong the shelf-life and maintain the nutritional quality of lipid-containing foods, and to modulate the consequences of oxidative damage in the human body. The term antioxidant can be defined as a substance that, when present at low concentrations (compared with those of an oxidizable substrate), can significantly delay or prevent oxidation of that substrate. Many substances have been suggested to act as antioxidants in vivo, and methods are now available for assessing their effectiveness in physiologically scavenging important biological oxygen-derived species. Oxygen-derived species have been grouped together (Halliwell) and called reactive oxygen species’ (ROS). They include: superoxide (02~•) and hydroxyl (OH•) radicals, and also hydrogen peroxide (H202), hypochlorous acid (HOCl), haemassociated ferryl species, and radicals derived from activated phagocytes, and peroxyl radicals (both lipid-soluble and water-soluble). In practice, interaction and balance between oxygen- and nitrogen-derived reactive species are intimately related, and both play an important and interrelated role in pathophysiology. Reactive nitrogen species’ include: nitric oxide (NO•) and nitrogen dioxide (NO2•) radicals, as well as a number of non-radicals such as nitrous oxide (HN02) and peroxynitrites (ONOO). The role in pathology, particularly of peroxynitrites, is now recognized as being important. The main route of formation of NO is by NO synthase; its role in physiology and pathology, and the properties that interfere with its synthesis, are described in more detail elsewhere. See NEUROPROTECTIVE AGENTS; NITRERGIC STIMULANTS; NITRIC OXIDE SYNTHASE INHIBITORS.

Free-radicals are formed in vivo, and an imbalance between production of ROS and antioxidant defence can result in oxidative stress. This may arise either from deficiencies of natural antioxidants (e.g. glutathione, ascorbate or α-tocopherol), and/or from increased formation of ROS. Oxidative stress can result in glutathione depletion, lipid peroxidation, membrane damage and DNA strand breaks; as well as activation of proteases, nucleases and protein kinases. It is now accepted that some degree of oxidative stress occurs in most human diseases, and a major question is whether it makes a significant contribution to the disease pathology. In the case of atherosclerosis, evidence from studies with the chain-breaking antioxidant probucol. and from epidemiological work, suggests that oxidative damage does indeed make an important contribution to vascular plaque development Antioxidant defences, both enzymic and nonenzymic, protect the body against oxidative damage, but they are not fully efficient, and so free-radical damage must be constantly repaired. Nonenzymatic antioxidants are frequently added to foods to prevent lipid peroxidation but the effect of such antioxidants on human disease states is not yet well evaluated. A number of antioxidant molecules are being evaluated in disease states, and even the enzyme superoxide dismutase (SOD) has been used in experimental studies (as orgotein, from bovine liver sources, or a human decombinant technology version of N-acetylsuperoxide dismutase known as sudismase).

In terms of generation of free-radicals, nitric oxide has increasingly been a subject of research. NO is emerging as an important regulator of a number of physiological processes. However, under conditions of inappropriate or excessive formation, nitric oxide is also now recognized as an important mediator of pathological nervous tissue damage. The main formation of NO by NO synthase and NO donors is discussed elsewhere (see NITRIC OXIDE SYNTHASE INHIBITORS; NITRERGIC STIMULANTS). NO can exert autocrine or more commonly paracrine effects. At low concentrations, NO mediates effects through activating guanylyl cyclase to elevate cGMR Such effects are wide-ranging and are normally cytoprotective, generally leading to reduced cellular reaction to intracellular calcium level. Nitric oxide can be produced in NO• or NO• forms, depending on the redox state of the cell. In neurons, the NO• form has a negative effect on NMDA receptors, tending to close the channel, so NO is cytoprotective/neuroprotective under such circumstances. It is the NO• form that activates guanylyl cyclase, leading to generally benign effects on the cell. However, the NO• form reacts with superoxide anion (02•) to form the peroxynitrite radical (ONOO), a potent oxidant that mediates some of either the protective or cytotoxic effects of NO. The cytotoxic effects can be beneficial when used in host defence (e.g. from activated leucocytes, both neutrophils and monocytes, in host defence against tumour cells, and pathogenic organisms including bacteria, fungi, protozoa and metazoan parasites). However, excessive biosynthesis of NO due to overstimulation of NMDA receptors is excitotoxic, for instance in ischaemic brain damage (stroke), it leads to overproduction of NO which can be cytotoxic. The cytotoxic effects of NO mediated via the peroxynitrite radical include lipid peroxidation, nitrosylation of nucleic acids, and combination with haem-containing enzymes including those involved in cell respiration. Production of peroxynitrite anion is normally limited by the enzyme superoxide dismutase (SOD) which converts it to H202, and it is then broken down by the enzyme catalase. Another influence tending to offset the effects of NO production is its reaction with haemoglobin.