For a number of years, inosine, a purine nucleoside, has been marketed by health and dietary supplement distributors as an energy or performance enhancer although there is little scientific evidence that inosine has these properties. Recently, interest has been raised in the possibility that inosine may have therapeutic effects in neurodegenerative disorders, such as multiple sclerosis (MS), through its metabolic product uric acid (UA), a natural inhibitor of peroxynitrite. The highly reactive oxidant peroxynitrite contributes to the pathogenesis of MS and animal models of central nervous system (CNS) inflammation through damaging tissue as well as inducing functional changes in the blood-brain barrier (BBB) that facilitate inflammatory cell invasion into CNS tissues. UA is an intermediate of purine metabolism in lower mammals but the excreted end product in humans. Consequently, serum levels of UA are normally relatively high in humans, offering natural protection against ONOO- -mediated pathological processes. With respect to this concept, it is notable that MS patients most often have lower serum UA levels than age- and sex- matched healthy controls and gout (hyperuricemia) patients rarely, if ever, develop MS. These observations have led us to examine the possibility that raising serum UA levels in MS patients using inosine may have therapeutic value. An FDA-approved clinical trial concerning the use of inosine to treat MS is now underway. In addition, publication of the results of these ongoing studies has evidently resulted in a number of individuals with MS independently taking inosine purchased over-the-counter. Nevertheless, little effort has been made to determine whether or not oral ingestion of inosine has therapeutic effects that are consistent with those of UA in animal models of CNS inflammation. The objective of this proposal is therefore to test the validity of two plausible hypotheses concerning the therapeutic effects of inosine ingestion on neuroinflammatory diseases believed to involve peroxynitrite: 1/inosine is therapeutic by raising serum UA levels and inactivating peroxynitrite; 2/inosine is therapeutic by suppressing the immune functions responsible for disease pathogenesis.
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