Aminoguanidine, an inhibitor of inducible nitric oxide synthase, ameliorates experimental autoimmune encephalomyelitis in SJL mice

Previous work from our laboratory localized nitric oxide to the affected spinal cords of mice with experimental autoimmune encephalomyelitis, a prime model for the human disease multiple sclerosis. The present study shows that activated lymphocytes sensitized to the central nervous system encephalit...

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Bibliographic Details
Published in:The Journal of clinical investigation 1994-06, Vol.93 (6), p.2684-2690
Main Authors: Cross, A H, Misko, T P, Lin, R F, Hickey, W F, Trotter, J L, Tilton, R G
Format: Article
Language:English
Subjects:
Amino Acid Oxidoreductases - antagonists & inhibitors
Animals
Encephalomyelitis, Autoimmune, Experimental - etiology
Encephalomyelitis, Autoimmune, Experimental - pathology
Encephalomyelitis, Autoimmune, Experimental - prevention & control
Female
Guanidines - pharmacology
Mice
Nitrates - blood
Nitric Oxide - physiology
Nitric Oxide Synthase
Nitrites - blood
Spinal Cord - pathology
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Summary:Previous work from our laboratory localized nitric oxide to the affected spinal cords of mice with experimental autoimmune encephalomyelitis, a prime model for the human disease multiple sclerosis. The present study shows that activated lymphocytes sensitized to the central nervous system encephalitogen, myelin basic protein, can induce nitric oxide production by a murine macrophage cell line. Induction was inhibited by amino-guanidine, a preferential inhibitor of the inducible nitric oxide synthase isoform, and by NG-monomethyl-L-arginine. Aminoguanidine, when administered to mice sensitized to develop experimental autoimmune encephalomyelitis, inhibited disease expression in a dose-related manner. At 400 mg aminoguanidine/kg per day, disease onset was delayed and the mean maximum clinical score was 0.9 +/- 1.2 in aminoguanidine versus 3.9 +/- 0.9 in placebo-treated mice. Histologic scoring of the spinal cords for inflammation, demyelination, and axonal necrosis revealed significantly less pathology in the aminoguanidine-treated group. The present study implicates excessive nitric oxide production in the pathogenesis of murine inflammatory central nervous system demyelination, and perhaps in the human disease multiple sclerosis.
ISSN:0021-9738
1558-8238
DOI:10.1172/jci117282