S-nitrosoglutathione prevents blood-brain barrier disruption associated with increased matrix metalloproteinase-9 activity in experimental diabetes

被引:32
作者
Aggarwal, Aanchal [1 ]
Khera, Alka [1 ]
Singh, Inderjit [2 ]
Sandhir, Rajat [1 ]
机构
[1] Panjab Univ, Dept Biochem, Chandigarh 160014, India
[2] Med Univ S Carolina, Dept Pediat, Charleston, SC 29425 USA
关键词
blood-brain barrier; cognition; diabetes; GSNO; matrix metalloproteinases; tissue inhibitor of matrix metalloproteinases; FOCAL CEREBRAL-ISCHEMIA; GLYCATION END-PRODUCTS; MATRIX METALLOPROTEINASES; OXIDATIVE STRESS; RAT MODEL; NEUROVASCULAR UNIT; TISSUE INHIBITORS; NERVOUS-SYSTEM; NITRIC-OXIDE; PERMEABILITY;
D O I
10.1111/jnc.12939
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 mu g/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.
引用
收藏
页码:595 / 608
页数:14
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