Prevention of experimental allergic encephalomyelitis by targeting nitric oxide and peroxynitrite: implications for the treatment of multiple sclerosis.
In this study we provide further evidence associating activated cells of the monocyte lineage with the lesions of multiple sclerosis (MS). Using a combination of immunohistochemistry and reverse transcriptase-dependent in situ polymerase chain reaction analysis, we have identified monocytes expressing inducible nitric oxide synthase (iNOS) to be prevalent in the plaque areas of post mortem brain tissue from patients with MS. In addition, we have obtained evidence of the nitration of tyrosine residues in brain areas local to accumulations of iNOS-positive cells. In parallel studies we have assessed the effects of inhibitors of iNOS induction, as well as scavengers of nitric oxide and peroxynitrite in the experimental allergic encephalomyelitis model. Significant therapeutic effects were seen with the inhibitor of iNOS induction, tricyclodecan-9-xyl-xanthogenate, a nitric oxide scavenger, 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide, and a peroxynitrite scavenger, uric acid. In particular, treatment with high doses of uric acid virtually prevented clinical symptoms of the disease. Together with our demonstration of the presence of activated macrophages expressing high levels of iNOS and evidence of peroxynitrite formation in brain tissue from patients with MS, these findings are of importance in the development of approaches to treat this disease.
Hooper
D C
DC
Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Bagasra
O
O
Marini
J C
JC
Zborek
A
A
Ohnishi
S T
ST
Kean
R
R
Champion
J M
JM
Sarker
A B
AB
Bobroski
L
L
Farber
J L
JL
Akaike
T
T
Maeda
H
H
Koprowski
H
H
D000818:Animals; D001921:Brain / Q000201:enzymology* / Q000473:pathology; D001952:Bridged-Ring Compounds / Q000627:therapeutic use*; D003497:Cyclic N-Oxides / Q000627:therapeutic use*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000201:enzymology / Q000517:prevention & control*; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D016166:Free Radical Scavengers; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D051379:Mice; D008815:Mice, Inbred Strains; D009000:Monocytes / Q000201:enzymology / Q000473:pathology; D009103:Multiple Sclerosis / Q000201:enzymology* / Q000473:pathology; D009566:Nitrates / Q000378:metabolism*; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis*; D009636:Norbornanes; D016133:Polymerase Chain Reaction / Q000379:methods; D012333:RNA, Messenger / Q000096:biosynthesis; D013116:Spinal Cord / Q000201:enzymology; D013859:Thiocarbamates; D013871:Thiones / Q000627:therapeutic use*; D014158:Transcription, Genetic; D014527:Uric Acid / Q000494:pharmacology* / Q000627:therapeutic use
D001952:Bridged-Ring Compounds; D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers; D007093:Imidazoles; D009566:Nitrates; D009636:Norbornanes; D012333:RNA, Messenger; D013859:Thiocarbamates; D013871:Thiones; C079391:2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide; C039642:peroxynitric acid; D014527:Uric Acid; D009569:Nitric Oxide; C046498:tricyclodecane-9-yl-xanthogenate; D019001:Nitric Oxide Synthase