Abstract
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.
© 2012 The Authors Journal of Neurochemistry © International Society for Neurochemistry.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Blood-Brain Barrier / drug effects*
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Blood-Brain Barrier / physiopathology
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Brain / drug effects
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Brain / metabolism
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Brain / pathology
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Brain Edema / drug therapy
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Brain Edema / etiology
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Carrier Proteins / metabolism
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Disease Models, Animal
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E-Selectin / metabolism
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Endothelial Cells / drug effects
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Endothelial Cells / metabolism
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Evans Blue
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Functional Laterality
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Infarction, Middle Cerebral Artery / complications
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Infarction, Middle Cerebral Artery / drug therapy
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Infarction, Middle Cerebral Artery / pathology*
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Male
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Matrix Metalloproteinase 9 / metabolism
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NF-kappaB-Inducing Kinase
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Neoplasm Proteins / metabolism
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Neurons / drug effects
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Neurons / metabolism
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Neuroprotective Agents / pharmacology*
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Neuroprotective Agents / therapeutic use
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Nitric Oxide / metabolism
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Nitrites / metabolism
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Nucleocytoplasmic Transport Proteins / metabolism
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Peroxynitrous Acid / metabolism*
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Phosphopyruvate Hydratase / metabolism
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Protein Serine-Threonine Kinases / metabolism
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Protein Transport / drug effects
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Rats
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Rats, Sprague-Dawley
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S-Nitrosoglutathione / pharmacology*
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Statistics, Nonparametric
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Time Factors
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Tyrosine / analogs & derivatives
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Tyrosine / metabolism
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Zonula Occludens-1 Protein / metabolism
Substances
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Carrier Proteins
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E-Selectin
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Neoplasm Proteins
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Neuroprotective Agents
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Nitrites
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Nucleocytoplasmic Transport Proteins
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Tjp1 protein, rat
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Zonula Occludens-1 Protein
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p65 oncofetal mRNA transport protein, rat
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stress-activated protein kinase-interacting protein, mouse
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Peroxynitrous Acid
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Nitric Oxide
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3-nitrotyrosine
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Tyrosine
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Evans Blue
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S-Nitrosoglutathione
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Protein Serine-Threonine Kinases
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Matrix Metalloproteinase 9
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Phosphopyruvate Hydratase