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

被引:331
作者
Hooper, DC
Scott, GS
Zborek, A
Mikheeva, T
Kean, RB
Koprowski, H
Spitsin, SV
机构
[1] Thomas Jefferson Univ, Dept Microbiol & Immunol, Kimmel Canc Inst, Philadelphia, PA 19107 USA
[2] Thomas Jefferson Univ, Biotechnol Fdn Labs, Philadelphia, PA 19107 USA
关键词
autoimmunity; encephalomyelitis; demyelinating diseases; multiple sclerosis; blood-brain barrier; uric acid;
D O I
10.1096/fasebj.14.5.691
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Peroxynitrite (ONOO-), a toxic product of the free radicals nitric oxide and superoxide, has been implicated in the pathogenesis of CNS inflammatory diseases, including multiple sclerosis and its animal correlate experimental autoimmune encephalomyelitis (EAE). In this study we have assessed the mode 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 into the CNS and prevents development of the disease. In mice with active EAE, exogenously administered UA penetrates the already compromised blood-CNS barrier, blocks ONOO--mediated tyrosine nitration and apoptotic cell death in 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 pathology is minimized; and 2) through a compromised blood-CNS barrier, by scavenging the ONOO- directly responsible for CNS tissue damage and death.-Hooper, D. C., Scott, G. S., Zborek, A., Mikheeva, T., Kean, R. B., Koprowski, H., Spitsin, S. V. Uric acid, a peroxynitrite scavenger, inhibits CNS inflammation, blood-CNS barrier permeability changes, and tissue damage in a mouse model of multiple sclerosis. FASEB J. 14, 691-698 (2000)
引用
收藏
页码:691 / 698
页数:8
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