Reaction of Uric Acid with Peroxynitrite and Implications for the Mechanism of Neuroprotection by Uric Acid

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Peroxynitrite, a biological oxidant formed from the reaction of nitric oxide with the superoxide radical, is associated with many pathologies, including neurodegenerative diseases, such as multiple sclerosis (MS). Gout (hyperuricemic) and MS are almost mutually exclusive, and uric acid has therapeutic effects in mice with experimental allergic encephalomyelitis, an animal disease that models MS. This evidence suggests that uric acid may scavenge peroxynitrite and/or peroxynitrite-derived reactive species. Therefore, we studied the kinetics of the reactions of peroxynitrite with uric acid from pH 6.9 to 8.0. The data indicate that peroxynitrous acid (HOONO) reacts with the uric acid monoanion with k = 155 M−1 s−1 (T = 37°C, pH 7.4) giving a pseudo-first-order rate constant in blood plasma kUrate/plasma = 0.05 s−1 (T = 37°C, pH 7.4; assuming [uric acid]plasma = 0.3 mM). Among the biological molecules in human plasma whose rates of reaction with peroxynitrite have been reported, CO2 is one of the fastest with a pseudo-first-order rate constant kCO2/plasma = 46 s−1 (T = 37°C, pH 7.4; assuming [CO2]plasma = 1 mM). Thus peroxynitrite reacts with CO2 in human blood plasma nearly 920 times faster than with uric acid. Therefore, uric acid does not directly scavenge peroxynitrite because uric acid can not compete for peroxynitrite with CO2. The therapeutic effects of uric acid may be related to the scavenging of the radicals CO•−3 and NO•2 that are formed from the reaction of peroxynitrite with CO2. We suggest that trapping secondary radicals that result from the fast reaction of peroxynitrite with CO2 may represent a new and viable approach for ameliorating the adverse effects associated with peroxynitrite in many diseases.