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 affect ed 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 nervo us system encephalitogen, myelin basic protein, can induce nitric oxid e production by a murine macrophage cell line. Induction was inhibited by aminoguanidine, a preferential inhibitor of the inducible nitric o xide synthase isoform, and by N-G-monomethyl-L-arginine. Aminoguanidin e, when administered to mice sensitized to develop experimental autoim mune encephalomyelitis, inhibited disease expression in a dose-related manner. At 100 mg aminoguanidine/kg per day, disease onset was delaye d 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 sp inal cords for inflammation, demyelination, and axonal necrosis reveal ed significantly less pathology in the aminoguanidine-treated group. T he present study implicates excessive nitric oxide production in the p athogenesis of murine inflammatory central nervous system demyelinatio n, and perhaps in the human disease multiple sclerosis.