The role of uric acid in protection against peroxynitrite-mediated pathology

Peroxynitrite, the product of the free radicals nitric oxide and superoxide , has been implicated in the pathogenesis of inflammatory CNS disorders. Ur ic acid, an effective scavenger of peroxynitrite, is a purine metabolite pr esent at high levels in the serum of hominoids relative to lower-order anim als due to the functional deletion of urate oxidase. Raising the normally l ow levels of uric acid in mice is therapeutic for experimental allergic enc ephalomyelitis, an animal model of multiple sclerosis. This therapeutic act ivity of uric acid is associated with the inhibition of peroxynitrite-induc ed tissue damage, blood-CNS barrier permeability changes, and CNS inflammat ion. Based on these findings we have concluded that peroxynitrite has an im portant role in promoting enhanced vascular permeability and inflammatory c ell extravasation. We hypothesize that higher uric acid levels in hominoids evolved to protect against this process. (C) 2001 Harcourt Publishers Ltd.