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

Anne H. Cross, Thomas P. Misko, Robin F. Lin, William F. Hickey, John L. Trotter, Ronald Tilton

Research output: Contribution to journalArticle

346 Citations (Scopus)

Abstract

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 aminoguanidine, a preferential inhibitor of the inducible nitric oxide synthase isoform, and by N(G)-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.

Original languageEnglish (US)
Pages (from-to)2684-2690
Number of pages7
JournalJournal of Clinical Investigation
Volume93
Issue number6
StatePublished - Jun 1994
Externally publishedYes

Fingerprint

Autoimmune Experimental Encephalomyelitis
Nitric Oxide Synthase Type II
Nitric Oxide
Demyelinating Diseases
Multiple Sclerosis
Central Nervous System
Myelitis
Myelin Basic Protein
Arginine
Spinal Cord
Protein Isoforms
Necrosis
Macrophages
Placebos
pimagedine
Lymphocytes
Pathology
Cell Line

Keywords

  • allergic encephalomyelitis
  • autoimmune diseases
  • demyelinating diseases
  • multiple sclerosis
  • nitric oxide

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Cross, A. H., Misko, T. P., Lin, R. F., Hickey, W. F., Trotter, J. L., & Tilton, R. (1994). Aminoguanidine, an inhibitor of inducible nitric oxide synthase, ameliorates experimental autoimmune encephalomyelitis in SJL mice. Journal of Clinical Investigation, 93(6), 2684-2690.

Aminoguanidine, an inhibitor of inducible nitric oxide synthase, ameliorates experimental autoimmune encephalomyelitis in SJL mice. / Cross, Anne H.; Misko, Thomas P.; Lin, Robin F.; Hickey, William F.; Trotter, John L.; Tilton, Ronald.

In: Journal of Clinical Investigation, Vol. 93, No. 6, 06.1994, p. 2684-2690.

Research output: Contribution to journalArticle

Cross, AH, Misko, TP, Lin, RF, Hickey, WF, Trotter, JL & Tilton, R 1994, 'Aminoguanidine, an inhibitor of inducible nitric oxide synthase, ameliorates experimental autoimmune encephalomyelitis in SJL mice', Journal of Clinical Investigation, vol. 93, no. 6, pp. 2684-2690.
Cross, Anne H. ; Misko, Thomas P. ; Lin, Robin F. ; Hickey, William F. ; Trotter, John L. ; Tilton, Ronald. / Aminoguanidine, an inhibitor of inducible nitric oxide synthase, ameliorates experimental autoimmune encephalomyelitis in SJL mice. In: Journal of Clinical Investigation. 1994 ; Vol. 93, No. 6. pp. 2684-2690.
@article{e4b4b112815846018ddea163afcc1104,
title = "Aminoguanidine, an inhibitor of inducible nitric oxide synthase, ameliorates experimental autoimmune encephalomyelitis in SJL mice",
abstract = "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 aminoguanidine, a preferential inhibitor of the inducible nitric oxide synthase isoform, and by N(G)-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.",
keywords = "allergic encephalomyelitis, autoimmune diseases, demyelinating diseases, multiple sclerosis, nitric oxide",
author = "Cross, {Anne H.} and Misko, {Thomas P.} and Lin, {Robin F.} and Hickey, {William F.} and Trotter, {John L.} and Ronald Tilton",
year = "1994",
month = "6",
language = "English (US)",
volume = "93",
pages = "2684--2690",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "6",

}

TY - JOUR

T1 - Aminoguanidine, an inhibitor of inducible nitric oxide synthase, ameliorates experimental autoimmune encephalomyelitis in SJL mice

AU - Cross, Anne H.

AU - Misko, Thomas P.

AU - Lin, Robin F.

AU - Hickey, William F.

AU - Trotter, John L.

AU - Tilton, Ronald

PY - 1994/6

Y1 - 1994/6

N2 - 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 aminoguanidine, a preferential inhibitor of the inducible nitric oxide synthase isoform, and by N(G)-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.

AB - 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 aminoguanidine, a preferential inhibitor of the inducible nitric oxide synthase isoform, and by N(G)-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.

KW - allergic encephalomyelitis

KW - autoimmune diseases

KW - demyelinating diseases

KW - multiple sclerosis

KW - nitric oxide

UR - http://www.scopus.com/inward/record.url?scp=0028360840&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0028360840&partnerID=8YFLogxK

M3 - Article

VL - 93

SP - 2684

EP - 2690

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 6

ER -