GSNO attenuates EAE disease by S-nitrosylation-mediated modulation of endothelial-monocyte interactions.
S-Nitrosoglutathione (GSNO) is an endogenous nitric oxide carrier and recently, has been documented for its anti-inflammatory effects in rat model of cerebral ischemia (Khan et al. (2005) J Cereb Blood Flow Metab 25:177-192). Here, we explored the neuroprotective effects mediated by GSNO in Lewis rat model of EAE and its mechanism of action using in vitro model of monocyte-endothelial cell interaction. Oral administration of GSNO attenuated the clinical disease course in EAE animals by inhibiting the infiltration of vascular immune cells in the CNS that subsequently led to the reduction in the expression of proinflammatory cytokines and consequently limited demyelination. Based on the inhibition in infiltration of immune cells, we hypothesized that GSNO modulated endothelial cell activation that led to reduce cellular infiltration in the CNS. Using an in vitro model, we established that GSNO inhibited monocyte adhesion to the activated endothelial cell, which was mediated by down regulation of endothelial cell adhesion molecules (CAMs). The mechanism by which GSNO modulated CAMs expression appeared to be via S-nitrosylation of p65, which consequently inhibited nuclear factor kappa B (NF-kappaB) activation in endothelial cells. These observations suggest that GSNO exerts its protective effects in EAE by inhibition of cellular infiltration into the CNS by S-nitrosylation of p65, thereby modulating NF-kappaB-CAMs pathway in endothelial cells.
Prasad
Ratna
R
Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
Giri
Shailendra
S
Nath
Narender
N
Singh
Inderjit
I
Singh
Avtar K
AK
D000284:Administration, Oral; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000502:physiology; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D002490:Central Nervous System / Q000187:drug effects* / Q000276:immunology / Q000503:physiopathology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D051379:Mice; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology / Q000627:therapeutic use; D009574:Nitro Compounds / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D026422:S-Nitrosoglutathione / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051996:Transcription Factor RelA / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D015815:Cell Adhesion Molecules; D016328:NF-kappa B; D020030:Nitric Oxide Donors; D009574:Nitro Compounds; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D026422:S-Nitrosoglutathione