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S ‐nitrosoglutathione prevents blood–brain barrier disruption associated with increased matrix metalloproteinase‐9 activity in experimental diabetes
Author(s) -
Aggarwal Aanchal,
Khera Alka,
Singh Inderjit,
Sandhir Rajat
Publication year - 2015
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/jnc.12939
Subject(s) - blood–brain barrier , matrix metalloproteinase , endocrinology , diabetes mellitus , morris water navigation task , medicine , streptozotocin , vascular permeability , intraperitoneal injection , gelatinase , hippocampus , chemistry , central nervous system
Abstract Hyperglycemia is known to induce microvascular complications, thereby altering blood–brain barrier (BBB) permeability. This study investigated the role of matrix metalloproteinases (MMPs) and their endogenous inhibitors in increased BBB permeability and evaluated the protective effect of S ‐nitrosoglutathione (GSNO) in diabetes. Diabetes was induced in mice by intraperitoneal injection of streptozotocin (40 mg/kg body weight) for 5 days and GSNO was administered orally (100 μg/kg body weight) daily for 8 weeks after the induction of diabetes. A significant decline in cognitive functions was observed in diabetic mice assessed by Morris water maze test. Increased permeability to different molecular size tracers accompanied by edema and ion imbalance was observed in cortex and hippocampus of diabetic mice. Furthermore, activity of both pro and active MMP‐9 was found to be significantly elevated in diabetic animals. Increased in situ gelatinase activity was observed in tissue sections and isolated microvessels from diabetic mice brain. The increase in activity of MMP‐9 was attributed to increased mRNA and protein expression in diabetic mice. In addition, a significant decrease in mRNA and protein expression of tissue inhibitor of matrix metalloproteinase‐1 was also observed in diabetic animals. However, GSNO supplementation to diabetic animals was able to abridge MMP‐9 activation as well as tissue inhibitor of matrix metalloproteinase‐1 levels, restoring BBB integrity and also improving learning and memory. Our findings clearly suggest that GSNO could prevent hyperglycemia‐induced disruption of BBB by suppressing MMP‐9 activity.Hyperglycemia is known to induce microvascular complications, thereby altering blood–brain barrier (BBB) permeability. In the present study, we have shown that this effect occurred through increased matrix metalloproteinase 9 (MMP‐9) and decreased tissue inhibitor of matrix metalloproteinase (TIMP‐1) levels, leading to cognitive deficits. S‐nitrosoglutathione (GSNO) was able to abridge MMP‐9 activation and TIMP‐1 levels, thereby restoring BBB integrity and improving learning and memory. GSNO could thus be beneficial in hyperglycemia‐induced encephalopathy. STZ, Streptozotocin.