Chen Bin, Wang Guoxiang, Li Weiwei, Liu Weilin, Lin Ruhui, Tao Jing, Jiang Min, Chen Lidian, Wang Yun
Fujian Rehabilitation Tech Co-innovation Center (2011 Project), Fujian Rehabilitation Engineering Research Center & Fujian Key Lab of Motor Function Rehabilitation, Academy of Integrative Medicine Biomedical Research Center, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China; Institutes of Brain Science and State Key Laboratory for Medical Neurobiology, Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China.
Institutes of Brain Science and State Key Laboratory for Medical Neurobiology, Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China.
Exp Cell Res. 2017 Feb 15;351(2):163-172. doi: 10.1016/j.yexcr.2016.12.028. Epub 2017 Jan 6.
Ischemic stroke, the second leading cause of death worldwide, leads to excessive glutamate release, over-activation of N-methyl-D-aspartate receptor (NMDAR), and massive influx of calcium (Ca), which may activate calpain and caspase-3, resulting in cellular damage and death. Memantine is an uncompetitive NMDAR antagonist with low-affinity/fast off-rate. We investigated the potential mechanisms through which memantine protects against ischemic stroke in vitro and in vivo. Middle cerebral artery occlusion-reperfusion (MCAO) was performed to establish an experimental model of ischemic stroke. The neuroprotective effects of memantine on ischemic rats were evaluated by neurological deficit scores and infarct volumes. The activities of calpain and caspase-3, and expression levels of microtubule-associated protein-2 (MAP2) and postsynaptic density-95 (PSD95) were determined by Western blotting. Additionally, Nissl staining and immunostaining were performed to examine brain damage, cell apoptosis, and neuronal loss induced by ischemia. Our results show that memantine could significantly prevent ischemic stroke-induced neurological deficits and brain infarct, and reduce ATP depletion-induced neuronal death. Moreover, memantine markedly suppressed the activation of the calpain-caspase-3 pathway and cell apoptosis, and consequently, attenuated brain damage and neuronal loss in MCAO rats. These results provide a molecular basis for the role of memantine in reducing neuronal apoptosis and preventing neuronal damage, suggesting that memantine may be a promising therapy for stroke patients.
缺血性中风是全球第二大致死原因，会导致谷氨酸过度释放、N-甲基-D-天冬氨酸受体（NMDAR）过度激活以及大量钙（Ca）内流，这可能会激活钙蛋白酶和半胱天冬酶-3，导致细胞损伤和死亡。美金刚是一种具有低亲和力/快速解离速率的非竞争性NMDAR拮抗剂。我们研究了美金刚在体外和体内预防缺血性中风的潜在机制。采用大脑中动脉闭塞-再灌注（MCAO）建立缺血性中风实验模型。通过神经功能缺损评分和梗死体积评估美金刚对缺血大鼠的神经保护作用。通过蛋白质免疫印迹法测定钙蛋白酶和半胱天冬酶-3的活性以及微管相关蛋白-2（MAP2）和突触后致密蛋白95（PSD95）的表达水平。此外，进行尼氏染色和免疫染色以检查缺血诱导的脑损伤、细胞凋亡和神经元损失。我们的结果表明，美金刚可以显著预防缺血性中风诱导的神经功能缺损和脑梗死，并减少ATP耗竭诱导的神经元死亡。此外，美金刚显著抑制钙蛋白酶-半胱天冬酶-3途径的激活和细胞凋亡，从而减轻MCAO大鼠的脑损伤和神经元损失。这些结果为美金刚在减少神经元凋亡和预防神经元损伤中的作用提供了分子基础，表明美金刚可能是中风患者一种有前景的治疗方法。
