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 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.
Cross
A H
AH
Department of Neurology, Washington University School of Medicine, Saint Louis, Missouri 63110.
Misko
T P
TP
Lin
R F
RF
Hickey
W F
WF
Trotter
J L
JL
Tilton
R G
RG
D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors*; D000818:Animals; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D006146:Guanidines / Q000494:pharmacology*; D051379:Mice; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase; D009573:Nitrites / Q000097:blood; D013116:Spinal Cord / Q000473:pathology
D006146:Guanidines; D009566:Nitrates; D009573:Nitrites; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; C004479:pimagedine