Inhibition of nitric oxide synthase for treatment of experimental autoimmune encephalomyelitis.
Aminoguanidine (AG), a selective inhibitor of inducible nitric oxide synthase, prevented the clinical development of experimental autoimmune encephalomyelitis (EAE) with a reduction in inflammation and demyelination. Administration of AG reduced the expression of nitrosotyrosine in inflammatory lesions in the central nervous system. Cytokine expression, determined by semiquantitative PCR, revealed increased expression of IFN-gamma, IL-10, and TGF-beta, which was associated with protection from EAE, and reduced TNF-alpha, associated with the development of EAE. Furthermore, AG blocked the secretion of nitric oxide, TNF-alpha, and PGE2 in astrocyte cultures. AG did not influence the proliferation response of T cells to a pathogenic epitope of myelin basic protein. Down-regulation of nitric oxide by AG has widespread consequences for cytokine production in central nervous system inflammation and prevents EAE.
Brenner
T
T
Department of Neurology, Hadassah University Hospital, Jerusalem, Israel.
Brocke
S
S
Szafer
F
F
Sobel
R A
RA
Parkinson
J F
JF
Perez
D H
DH
Steinman
L
L
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D005260:Female; D006146:Guanidines / Q000494:pharmacology* / Q000627:therapeutic use; D008213:Lymphocyte Activation; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D010455:Peptides / Q000276:immunology; D016133:Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology; D014443:Tyrosine / Q000187:drug effects / Q000378:metabolism
D018946:Chemokine CCL5; D016207:Cytokines; D006146:Guanidines; D010455:Peptides; D009569:Nitric Oxide; D014443:Tyrosine; D019001:Nitric Oxide Synthase; C004479:pimagedine