A catalyst of peroxynitrite decomposition inhibits murine experimental autoimmune encephalomyelitis.
Peroxynitrite (PN), the product of nitric oxide (NO) reacted with superoxide, is generated at sites of inflammation. Nitrotyrosine (NT), a marker of PN formation, is abundant in lesions of acute experimental autoimmune encephalomyelitis (EAE), and in active multiple sclerosis (MS) plaques. To determine whether PN plays a role in EAE pathogenesis, mice induced to develop EAE were treated with a catalyst specific for the decomposition of PN. Because this catalyst has no effect upon NO, using it allowed differentiation of PN-mediated effects from NO-mediated effects. Mice receiving the PN decomposition catalyst displayed less severe clinical disease, and less inflammation and demyelination than control mice. Encephalitogenic T cells could be recovered from catalyst-treated mice, indicating that the PN decomposition catalyst blocked the pathogenic action of PN at the effector stage of EAE, but was not directly toxic to encephalitogenic T cells. PN plays an important role distinct from that of NO in the pathogenesis of EAE, a major model for MS.
Cross
A H
AH
Department of Neurology and Neurosurgery, Washington University School of Medicine, Box 8111, 660 S. Euclid, St. Louis, MO 63110, USA. crossa@neuro.wustl.edu
San
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Stern
M K
MK
Keeling
R M
RM
Salvemini
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Misko
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TP
D000818:Animals; D002384:Catalysis; D002490:Central Nervous System / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D005260:Female; D005290:Ferric Compounds / Q000494:pharmacology*; D007150:Immunohistochemistry; D017710:Lymphocyte Transfusion; D008214:Lymphocytes / Q000276:immunology; D008665:Metalloporphyrins / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D009566:Nitrates / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
C112917:5,10,15,20-tetrakis(2,4,6-trimethyl-3,3-disulfonatophenyl)porphyrinato iron(III); D005290:Ferric Compounds; D008665:Metalloporphyrins; D009566:Nitrates; C039642:peroxynitric acid; C002744:3-nitrotyrosine; D014443:Tyrosine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse