Uric acid, a peroxynitrite scavenger, inhibits CNS inflammation, blood-CNSbarrier permeability changes, and tissue damage in a mouse model of multiple sclerosis

Peroxynitrite (ONOO-), a toxic product of the free radicals nitric oxide an d superoxide, has been implicated in the pathogenesis of CNS inflammatory d iseases, including multiple sclerosis and its animal correlate experimental autoimmune encephalomyelitis (EAE). In this study we have assessed the mod e of action of uric acid (UA), a purine metabolite and ONOO- scavenger, in the treatment of EAE. We show that if administered to mice before the onset of clinical EAE, UA interferes with the invasion of inflammatory cells int o the CNS and prevents development of the disease. In mice with active EAE, exogenously administered UA penetrates the already compromised blood-CNS b arrier, blocks ONOO--mediated tyrosine nitration and apoptotic cell death i n areas of inflammation in spinal cord tissues and promotes recovery of the animals. Moreover, UA treatment suppresses the enhanced blood-CNS barrier permeability characteristic of EAE. We postulate that UA acts at two levels in EAE: 1) by protecting the integrity of the blood-CNS barrier from ONOO- -induced permeability changes such that cell invasion and the resulting pat hology is minimized; and 2) through a compromised blood-CNS barrier, by sca venging the ONOO- directly responsible for CNS tissue damage and death.-Hoo per, D. C., Scott, G. S., Zborek, A., Mikheeva, T., Kean, R. B., Koprowski, H., Spitsin, S. V. Uric acid, a peroxynitrite scavenger, inhibits CNS infl ammation, blood-CNS barrier permeability changes, and tissue damage in a mo use model of multiple sclerosis. FASEB J. 14, 691-698 (2000)