Therapeutic intervention in experimental allergic encephalomyelitis by administration of uric acid precursors.
Uric acid (UA) is a purine metabolite that selectively inhibits peroxynitrite-mediated reactions implicated in the pathogenesis of multiple sclerosis (MS) and other neurodegenerative diseases. Serum UA levels are inversely associated with the incidence of MS in humans because MS patients have low serum UA levels and individuals with hyperuricemia (gout) rarely develop the disease. Moreover, the administration of UA is therapeutic in experimental allergic encephalomyelitis (EAE), an animal model of MS. Thus, raising serum UA levels in MS patients, by oral administration of a UA precursor such as inosine, may have therapeutic value. We have assessed the effects of inosine, as well as inosinic acid, on parameters relevant to the chemical reactivity of peroxynitrite and the pathogenesis of EAE. Both had no effect on chemical reactions associated with peroxynitrite, such as tyrosine nitration, or on the activation of inflammatory cells in vitro. Moreover, when mice treated with the urate oxidase inhibitor potassium oxonate were fed inosine or inosinic acid, serum UA levels were elevated markedly for a period of hours, whereas only a minor, transient increase in serum inosine was detected. Administration of inosinic acid suppressed the appearance of clinical signs of EAE and promoted recovery from ongoing disease. The therapeutic effect on animals with active EAE was associated with increased UA, but not inosine, levels in CNS tissue. We, therefore, conclude that the mode of action of inosine and inosinic acid in EAE is via their metabolism to UA.
Scott
Gwen S
GS
Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Spitsin
Sergei V
SV
Kean
Rhonda B
RB
Mikheeva
Tatiana
T
Koprowski
Hilary
H
Hooper
D Craig
DC
D000284:Administration, Oral; D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D004353:Drug Evaluation, Preclinical; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007288:Inosine / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007291:Inosine Monophosphate / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051379:Mice; D008981:Molsidomine / Q000031:analogs & derivatives* / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D009103:Multiple Sclerosis / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010094:Oxonic Acid / Q000494:pharmacology; D030421:Peroxynitrous Acid / Q000378:metabolism; D014503:Urate Oxidase / Q000037:antagonists & inhibitors; D014527:Uric Acid / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology
D004791:Enzyme Inhibitors; D014970:Xanthines; D007291:Inosine Monophosphate; C018221:8-azaxanthine; D030421:Peroxynitrous Acid; D014527:Uric Acid; C470581:9-methyluric acid; D007288:Inosine; C002385:linsidomine; D010094:Oxonic Acid; D008981:Molsidomine; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D014503:Urate Oxidase