The list of pathophysiological conditions associated with the overproduction of
superoxide expands every day. Much of the knowledge compiled on the role of this radical in disease has been gathered using the native
superoxide dismutase enzyme and, more recently, by the use of
superoxide dismutase knockout models or transgenic models that overexpress the various
isoforms of the
enzyme. Although the native
enzyme has shown promising anti-inflammatory properties in both preclinical and clinical studies, there were drawbacks and issues associated with its use as a therapeutic agent and pharmacological tool. Based on the concept that removal of
superoxide modulates the course of
inflammation, synthetic, low-molecular-weight mimetics of the
superoxide dismutase enzymes that could overcome some of the limitations associated with the use of the native
enzyme have been designed. In this review, we will discuss the advances made using various
superoxide dismutase mimetics that led to the proposal that
superoxide (and/or the product of its interaction with
nitric oxide,
peroxynitrite) is an important mediator of
inflammation, and to the conclusion that
superoxide dismutase mimetics can be utilized as therapeutic agents in diseases of various etiologies. The importance of the selectivity of such compounds in pharmacological studies will be discussed.