Sod mimetics are coming of age

Key Points Under normal circumstances, formation of superoxide anions is kept under tight control by superoxide dismutase enzymes. These include the manganese (Mn) enzyme in mitochondria and the copper (Cu)/zinc (Zn) enzyme that is present in the cytosol or on extracellular surfaces. Superoxide anions are formed by means of several pathways, including through normal cellular respiration, by inflammatory cells, by endothelial cells and in the metabolism of arachidonic acid. Extensive scientific research over the past twenty years has shown that, in acute and chronic inflammation, superoxide anions are produced at a rate that overwhelms the capacity of the endogenous superoxide dismutase enzyme-defence system to remove them. Such an imbalance results in superoxide-mediated damage. Protective and beneficial roles of superoxide dismutase have been shown in a broad range of diseases, both preclinically and clinically. The results from the latter studies prove the concept that superoxide anions have an important role in human disease, and that their removal by the native enzyme does in fact result in beneficial outcomes. Although the native enzymes have shown promising anti-inflammatory properties in both preclinical and clinical studies in various diseases, there were drawbacks and issues that were associated with the use of the native enzymes as therapeutic agents and as pharmacological tools. On the basis that removing superoxide anions modulates the course of inflammation, synthetic, low-molecular-mass mimetics of the superoxide dismutase enzymes, which can overcome some of the limitations that are associated with the use of the native enzymes, have been developed as potential therapeutic agents. The list of pathophysiological conditions that are associated with the overproduction of superoxide anions expands every day. The most exciting realization is that there seems to be a similarity between the tissue injury that is observed in various disease states, as superoxide anions produce tissue injury and associated inflammation in all tissues in similar ways. Tissue injury and inflammation form the basis of many disease pathologies, including ischaemia and reperfusion injuries, radiation injury, hyperoxic lung damage and atherosclerosis. This commonality provides a unique opportunity to manipulate numerous disease states with an agent that removes superoxide anions.