S-nitrosoglutathione prevents blood-brain barrier disruption associated with increased matrix metalloproteinase-9 activity in experimental diabetes
S-nitrosoglutathione prevents blood-brain barrier disruption associated with increased matrix metalloproteinase-9 activity in experimental diabetes
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DOI：
10.1111/jnc.12939
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发表时间：
2015-03-01
影响因子：
4.7
通讯作者：
Sandhir, Rajat
中科院分区：
文献类型：
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作者：
Aggarwal, Aanchal;Khera, Alka;Sandhir, Rajat
已知高血压会诱导微血管并发症，从而改变血脑屏障（BBB）的通透性。本研究探讨了基质金属蛋白酶（MMPs）及其内源性抑制剂在血脑屏障通透性增加中的作用，并评价了S-亚硝基谷胱甘肽（GSNO）在糖尿病中的保护作用。通过腹膜内注射链脲佐菌素（40毫克/千克体重）5天诱导小鼠糖尿病，并在诱导糖尿病后每天口服GSNO（100微克/千克体重）8周。Morris水迷宫实验显示糖尿病小鼠认知功能明显下降。在糖尿病小鼠的皮层和海马中观察到对不同分子大小的示踪剂的通透性增加，伴随着水肿和离子失衡。此外，发现在糖尿病动物中MMP-9的前体和活性都显著升高。在糖尿病小鼠脑组织切片和分离的微血管中观察到原位明胶酶活性增加。MMP-9活性的增加归因于糖尿病小鼠中mRNA和蛋白表达的增加。此外，在糖尿病动物中还观察到基质金属蛋白酶组织抑制剂-1的mRNA和蛋白表达的显著降低。然而，对糖尿病动物补充GSNO能够缩短MMP-9活化以及基质金属蛋白酶-1水平的组织抑制剂，恢复BBB完整性并改善学习和记忆。我们的研究结果清楚地表明，GSNO可以通过抑制MMP-9活性来防止高血糖诱导的BBB破坏。
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.