The inhibitory effect of S-nitrosoglutathione on blood-brain barrier disruption and peroxynitrite formation in a rat model of experimental stroke.
The hallmark of stroke injury is endothelial dysfunction leading to blood-brain barrier (BBB) leakage and edema. Among the causative factors of BBB disruption are accelerating peroxynitrite formation and the resultant decreased bioavailability of nitric oxide (NO). S-nitrosoglutathione (GSNO), an S-nitrosylating agent, was found not only to reduce the levels of peroxynitrite but also to protect the integrity of BBB in a rat model of cerebral ischemia and reperfusion (IR). A treatment with GSNO (3 μmol/kg) after IR reduced 3-nitrotyrosine levels in and around vessels and maintained NO levels in brain. This mechanism protected endothelial function by reducing BBB leakage, increasing the expression of Zonula occludens-1 (ZO-1), decreasing edema, and reducing the expression of matrix metalloproteinase-9 and E-selectin in the neurovascular unit. An administration of the peroxynitrite-forming agent 3-morpholino sydnonimine (3 μmol/kg) at reperfusion increased BBB leakage and decreased the expression of ZO-1, supporting the involvement of peroxynitrite in BBB disruption and edema. Mechanistically, the endothelium-protecting action of GSNO was invoked by reducing the activity of nuclear factor kappa B and increasing the expression of S-nitrosylated proteins. Taken together, the results support the ability of GSNO to improve endothelial function by reducing nitroxidative stress in stroke.
Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
Mushfiquddin
M
Khan
Tajinder S
TS
Dhammu
Harutoshi
H
Sakakima
Anadakumar
A
Shunmugavel
Anne G
AG
Gilg
Avtar K
AK
Singh
Inderjit
I
Singh
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000503:physiopathology; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001929:Brain Edema / Q000188:drug therapy / Q000209:etiology; D002352:Carrier Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D019040:E-Selectin / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005070:Evans Blue; D007839:Functional Laterality; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000188:drug therapy / Q000473:pathology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D009569:Nitric Oxide / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D029543:Nucleocytoplasmic Transport Proteins / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000378:metabolism*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D026422:S-Nitrosoglutathione / Q000494:pharmacology*; D018709:Statistics, Nonparametric; D013997:Time Factors; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D062826:Zonula Occludens-1 Protein / Q000378:metabolism; D000097782:NF-kappaB-Inducing Kinase; D048868:Adaptor Proteins, Signal Transducing
D002352:Carrier Proteins; D019040:E-Selectin; D005070:Evans Blue; D020780:Matrix Metalloproteinase 9; D009363:Neoplasm Proteins; D018696:Neuroprotective Agents; D009569:Nitric Oxide; D009573:Nitrites; D029543:Nucleocytoplasmic Transport Proteins; D030421:Peroxynitrous Acid; D010751:Phosphopyruvate Hydratase; D017346:Protein Serine-Threonine Kinases; D026422:S-Nitrosoglutathione; D014443:Tyrosine; D062826:Zonula Occludens-1 Protein; D000097782:NF-kappaB-Inducing Kinase; C569044:Tjp1 protein, rat; C063447:p65 oncofetal mRNA transport protein, rat; C561937:Mapkap1 protein, mouse; D048868:Adaptor Proteins, Signal Transducing; C002744:3-nitrotyrosine