Reaction of uric acid with peroxynitrite and implications for the mechanism of neuroprotection by uric acid

Peroxynitrite, a biological oxidant formed from the reaction of nitric oxid e with the superoxide radical, is associated with many pathologies, includi ng neurodegenerative diseases, such as multiple sclerosis (MS), Gout (hyper uricemic) and MS are almost mutually exclusive, and uric acid has therapeut ic 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 wit h the uric acid monoanion with k = 155 M-1 s(-1) (T = 37 degrees C, pH 7.4) giving a pseudo-first-order rate constant in blood plasma k(Uratc/plasma) = 0.05 s(-1) (T = 37 degrees 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, CO, is one of the fastest with a ps eudo-first-order rate constant k(co2/plasma) = 46 s(-1) (T = 37 degrees 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. Therefor e, uric acid does not directly scavenge peroxynitrite because uric acid can not compete for peroxynitrite with CO,. The therapeutic effects of uric ac id may be related to the scavenging of the radicals CO3.- and NO; that are formed from the reaction of peroxynitrite with CO,. We suggest that trappin g secondary radicals that result from the fast reaction of peroxynitrite wi th CO, may represent a new and viable approach for ameliorating the adverse effects associated with peroxynitrite in many diseases. (C) 2000 Academic Press.