The peroxynitrite scavenger uric acid prevents inflammatory cell invasion into the central nervous system in experimental allergic encephalomyelitis through maintenance of blood-central nervous system barrier integrity

Uric acid (UA), a product of purine metabolism, is a known scavenger of per oxynitrite (ONOO-), which has been implicated in the pathogenesis of multip le sclerosis and experimental allergic encephalomyelitis (EAE), To determin e whether the known therapeutic action of UA in EAE is mediated through its capacity to inactivate ONOO- or some other immunoregulatory phenomenon, th e effects of UA on Ag presentation, T cell reactivity, Ab production, and e vidence of CNS inflammation were assessed. The inclusion of physiological l evels of UA in culture effectively inhibited ONOO--mediated oxidation as we ll as tyrosine nitration, which has been associated with damage in EAE and multiple sclerosis, but had no inhibitory effect on the T cell-proliferativ e response to myelin basic protein (MBP) or on APC function. In addition, U A treatment was found to have no notable effect on the development of the i mmune response to MBP in vivo, as measured by the production of MBP-specifi c Ab and the induction of MBP-specific T cells, The appearance of cells exp ressing mRNA for inducible NO synthase in the circulation of MBP-immunized mice was also unaffected by UA treatment. However, in UA-treated animals, t he blood-CNS barrier breakdown normally associated with EAE did not occur, and inducible NO synthase-positive cells most often failed to reach CNS tis sue. These findings are consistent with the notion that UA is therapeutic i n EAE by inactivating ONOO-, or a related molecule, which is produced by ac tivated monocytes and contributes to both enhanced blood-CNS barrier permea bility as well as CNS tissue pathology.