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. Uric acid, an effective scavenger of peroxynitrite, is a purine metabolite present at high levels in the serum of hominoids relative to lower-order animals due to the functional deletion of urate oxidase. Raising the normally low levels of uric acid in mice is therapeutic for experimental allergic encephalomyelitis, an animal model of multiple sclerosis. This therapeutic activity of uric acid is associated with the inhibition of peroxynitrite-induced tissue damage, blood-CNS barrier permeability changes, and CNS inflammation. Based on these findings we have concluded that peroxynitrite has an important role in promoting enhanced vascular permeability and inflammatory cell extravasation. We hypothesize that higher uric acid levels in hominoids evolved to protect against this process.
Scott
G S
GS
Department of Microbiology and Immunology and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Hooper
D C
DC
D000818:Animals; D006801:Humans; D051379:Mice; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D009566:Nitrates / Q000009:adverse effects*; D014527:Uric Acid / Q000378:metabolism*
D009566:Nitrates; C039642:peroxynitric acid; D014527:Uric Acid