Memantine mediates neuroprotection via regulating neurovascular unit in a mouse model of focal cerebral ischemia
Memantine mediates neuroprotection via regulating neurovascular unit in a mouse model of focal cerebral ischemia
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DOI：
10.1016/j.lfs.2016.02.081
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发表时间：
2016-04-01
期刊：
影响因子：
6.1
通讯作者：
Sun, Xiu-Lan
中科院分区：
文献类型：
--
作者：
Chen, Zheng-Zhen;Yang, Dan-Dan;Sun, Xiu-Lan
目的：美金刚是一种中低亲和力、非竞争性的N-甲基-D-天冬氨酸受体(NMDAR)拮抗剂，因其独特的作用模式，也是治疗急性缺血性卒中的潜在神经保护剂。本研究旨在揭示Memantine的神经保护作用机制。主要方法：采用小鼠大脑中动脉闭塞的永久性局灶性脑缺血模型来验证我们的假说。2，3，5-三苯基四氮唑氯化铵染色比较心肌梗死面积。用免疫组织化学和体视学方法分析星形胶质细胞的数量和小胶质细胞胞体的体积。Western blotting检测蛋白表达。主要发现：美金刚可预防脑缺血诱导的脑梗塞和神经元损伤，并减少缺氧缺糖诱导的皮质神经元凋亡。此外，美金刚还可减少缺血24 h损伤的星形胶质细胞数量和过度激活的小胶质细胞。在缺血的早期，观察到基质金属蛋白酶-9的高表达，从而使IV型胶原被显著破坏。同时，突触后密度蛋白95(PSD-95)也被严重切割。美金刚减少小鼠脑内基质金属蛋白酶-9的分泌，阻止IV型胶原的降解。意义：提示美金刚对急性缺血性脑损伤有神经保护作用，部分是通过改善神经血管单位的功能实现的。综上所述，我们认为美金刚可能是一种很有前途的缺血性卒中保护剂。(C)2016 Elsevier Inc.保留所有权利。
Aims: Memantine is a low-moderate affinity and uncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist, which is also a potential neuroprotectant in acute ischemic stroke for its particular action profiles. The present study was to reveal the mechanisms involved in the neuroprotection of memantine.Main methods: We used a mouse model of permanent focal cerebral ischemia via middle cerebral artery occlusion to verify our hypothesis. 2,3,5-Triphenyltetrazolium chloride staining was used to compare infarct size. The amount of astrocytes and the somal volume of the microglia cell body were analyzed by immunohistochemistry and stereological estimates. Western blotting was used to determine the protein expressions.Key findings: Memantine prevented cerebral ischemia-induced brain infarct and neuronal injury, and reduced oxygen-glucose deprivation-induced cortical neuronal apoptosis. Moreover, memantine reduced the amount of the damaged astrocytes and over activated microglia after 24 h of ischemia. In the early phase of ischemia, higher production of MMP-9 was observed, and thereby collagen IV was dramatically disrupted. Meanwhile, the post-synaptic density protein 95(PSD-95) was also severely cleavaged. Memantine decreased MMP-9 secretion, prevented the degradation of collagen IV in mouse brain. PSD-95 cleavage was also inhibited by memantine.Significance: These results suggested that memantine exerted neuroprotection effects in acute ischemic brain damage, partially via improving the functions of neurovascular unit. Taking all these findings together, we consider that memantine might be a promising protective agent against ischemic stroke. (C) 2016 Elsevier Inc. All rights reserved.