SIN-1, a nitric oxide donor, ameliorates experimental allergic encephalomyelitis in Lewis rats in the incipient phase: the importance of the time window.
NO is involved in the regulation of immune responses. The role of NO in the pathogenesis of experimental allergic encephalomyelitis (EAE) is controversial. In this study, 3-morpholinosydnonimine (SIN-1), an NO donor, was administered to Lewis rats on days 5-7 postimmunization, i.e., during the incipient phase of EAE. SIN-1 reduced clinical signs of EAE compared with those in PBS-treated control rats and was accompanied by reduced ED1(+) macrophages and CD4(+) T cell infiltration within the CNS. Blood mononuclear cells (MNC) obtained on day 14 postimmunization revealed that SIN-1 administration enhanced NO and IFN-gamma production by blood MNC and suppressed Ag- and mitogen-induced proliferative responses. MHC class II, B7-1 and B7-2 were down-regulated in SIN-1-treated EAE rats. Simultaneously, frequencies of apoptotic cells among blood MNC were increased. In vivo, SIN-1 is likely to behave as an NO donor. Administration of SIN-1 induced NO production, but did not affect superoxide and peroxynitrite formation. Enhanced NO production during the priming phase of EAE thus promotes apoptosis, down-regulates disease-promoting immune reactivities, and ameliorates clinical EAE, mainly through SIN-1-derived NO, without depending on NO synthase.
Xu
L Y
LY
Experimental Neurobiology and Neuroimmunology Units, Division of Neurology, Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden.
Yang
J S
JS
Link
H
H
Xiao
B G
BG
D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000627:therapeutic use; D000595:Amino Acid Sequence; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000627:therapeutic use; D015703:Antigens, CD / Q000096:biosynthesis; D018122:B7-1 Antigen / Q000096:biosynthesis; D051940:B7-2 Antigen; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D015536:Down-Regulation / Q000276:immunology; D004334:Drug Administration Schedule; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D006168:Guinea Pigs; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000627:therapeutic use; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000096:biosynthesis / Q000378:metabolism; D007958:Leukocyte Count; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008969:Molecular Sequence Data; D008981:Molsidomine / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000627:therapeutic use; D004676:Myelin Basic Protein / Q000276:immunology; D009569:Nitric Oxide / Q000096:biosynthesis; D020030:Nitric Oxide Donors / Q000008:administration & dosage* / Q000627:therapeutic use; D010446:Peptide Fragments / Q000276:immunology; D051381:Rats; D011917:Rats, Inbred Lew; D013116:Spinal Cord / Q000473:pathology
D000276:Adjuvants, Immunologic; D000894:Anti-Inflammatory Agents, Non-Steroidal; D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; C497966:Cd86 protein, rat; D000949:Histocompatibility Antigens Class II; D007166:Immunosuppressive Agents; D008562:Membrane Glycoproteins; D004676:Myelin Basic Protein; D020030:Nitric Oxide Donors; D010446:Peptide Fragments; C110235:myelin basic protein 68-86; D009569:Nitric Oxide; C002385:linsidomine; D007371:Interferon-gamma; D008981:Molsidomine