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The inhibitory effect of S‐nitrosoglutathione on blood–brain barrier disruption and peroxynitrite formation in a rat model of experimental stroke
Author(s) -
Khan Mushfiquddin,
Dhammu Tajinder S.,
Sakakima Harutoshi,
Shunmugavel Anadakumar,
Gilg Anne G.,
Singh Avtar K.,
Singh Inderjit
Publication year - 2012
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2012.07947.x
Subject(s) - peroxynitrite , s nitrosoglutathione , blood–brain barrier , inhibitory postsynaptic potential , stroke (engine) , chemistry , peroxynitrous acid , pharmacology , rat model , medicine , biochemistry , central nervous system , enzyme , glutathione , superoxide , mechanical engineering , engineering
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.