NMDA receptor subunits have differential roles in mediating excitotoxic neuronal death both in vitro and in vivo
NMDA receptor subunits have differential roles in mediating excitotoxic neuronal death both in vitro and in vivo
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DOI：
10.1523/jneurosci.0116-07.2007
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发表时间：
2007-03-14
影响因子：
5.3
通讯作者：
Wang, Yu Tian
中科院分区：
文献类型：
--
作者：
Liu, Yitao;Wong, Tak Pan;Wang, Yu Tian
来自中风的体外和体内模型的充分记录的实验证据强烈支持NMDA受体介导的兴奋性毒性在中风后神经元损伤中的关键参与。尽管如此，NMDA受体拮抗剂作为中风和脑创伤后神经保护剂的临床试验结果令人沮丧。在这里，我们报告说，在成熟的皮层文化，激活突触或突触外NR 2B-含有NMDA受体的兴奋性毒性的结果，增加神经元凋亡。相反，激活突触或突触外含有NR 2A的NMDA受体促进神经元存活，并对NMDA受体介导的和非NMDA受体介导的神经元损伤发挥神经保护作用。NR 2B和NR 2A在介导细胞死亡和细胞存活中的类似相反作用也在局灶性缺血性中风的体内大鼠模型中观察到。此外，我们发现，阻断NR 2B介导的细胞死亡是有效的，在减少梗死体积只有当受体拮抗剂中风发作前，而不是中风后4.5小时。与此形成鲜明对比的是，单独给予甘氨酸或在NR 2B拮抗剂存在下给予NR 2A介导的细胞存活信号的激活显著减弱了缺血性脑损伤，即使在中风发作后4.5小时递送。总之，目前的工作提供了一个分子基础的NMDA受体在促进神经元存活和介导的神经元损伤的双重作用，并表明，选择性增强NR 2A-含有NMDA受体的激活与甘氨酸可能构成一个有前途的治疗中风。
Well-documented experimental evidence from both in vitro and in vivo models of stroke strongly supports the critical involvement of NMDA receptor-mediated excitotoxicity in neuronal damage after stroke. Despite this, the results of clinical trials testing NMDA receptor antagonists as neuroprotectants after stroke and brain trauma have been discouraging. Here, we report that in mature cortical cultures, activation of either synaptic or extrasynaptic NR2B-containing NMDA receptors results in excitotoxicity, increasing neuronal apoptosis. In contrast, activation of either synaptic or extrasynaptic NR2A-containing NMDA receptors promotes neuronal survival and exerts a neuroprotective action against both NMDA receptor-mediated and non-NMDA receptor-mediated neuronal damage. A similar opposing action of NR2B and NR2A in mediating cell death and cell survival was also observed in an in vivo rat model of focal ischemic stroke. Moreover, we found that blocking NR2B-mediated cell death was effective in reducing infarct volume only when the receptor antagonist was given before the onset of stroke and not 4.5 h after stroke. In great contrast, activation of NR2A-mediated cell survival signaling with administration of either glycine alone or in the presence of NR2B antagonist significantly attenuated ischemic brain damage even when delivered 4.5 h after stroke onset. Together, the present work provides a molecular basis for the dual roles of NMDA receptors in promoting neuronal survival and mediating neuronal damage and suggests that selective enhancement of NR2A-containing NMDA receptor activation with glycine may constitute a promising therapy for stroke.