GLYX-13, a NMDA Receptor Glycine-Site Functional Partial Agonist, Attenuates Cerebral Ischemia Injury In Vivo and Vitro by Differential Modulations of NMDA Receptors Subunit Components at Different Post-Ischemia Stage in Mice.
GLYX-13, a NMDA Receptor Glycine-Site Functional Partial Agonist, Attenuates Cerebral Ischemia Injury In Vivo and Vitro by Differential Modulations of NMDA Receptors Subunit Components at Different Post-Ischemia Stage in Mice.
复制标题
GLYX-13 是一种 NMDA 受体甘氨酸位点功能部分激动剂，通过在小鼠缺血后不同阶段对 NMDA 受体亚基成分进行差异调节，减轻体内和体外脑缺血损伤。
DOI：
10.3389/fnagi.2017.00186
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发表时间：
2017
影响因子：
4.8
通讯作者：
Shen H
中科院分区：
文献类型：
--
作者：
Zheng C;Qiao ZH;Hou MZ;Liu NN;Fu B;Ding R;Li YY;Wei LP;Liu AL;Shen H
NMDA 受体 (NMDAR) 的过度激活与病理性突触可塑性（也称为缺血后长时程增强 (i-LTP)）有关，它是由中风后谷氨酸介导的兴奋性毒性产生的。在过去的几十年里，许多NMDARs抑制剂由于严重的拟精神病副作用而在临床研究中失败。 GLYX-13 是一种 NMDAR 调节剂，具有甘氨酸位点部分激动剂特性，对缺血性神经元死亡具有潜在的保护作用。然而，GLYX-13 减轻缺血性神经元损伤的潜在分子机制仍不清楚。我们的研究旨在检查 GLYX-13 在中风中的分子、细胞和行为作用，并通过调节 NMDAR 亚基组成进一步表征神经保护作用的机制。在本研究中，我们发现在体外氧糖剥夺（OGD）中风模型中，GLYX-13阻断i-LTP并恢复NR2A/NR2B亚基组成的比率。 NMDAR 完全共激动剂 D-丝氨酸的甘氨酸位点完全阻断了 GLYX-13 对 i-LTP 的作用。此外，在体内大脑中动脉闭塞（MCAO）模型中，GLYX-13减少了脑梗塞体积并减轻了海马损伤。 Western分析显示GLYX-13下调磷酸化NR2B (Tyr1472)的表达并上调磷酸化NR2A (Tyr1325)的表达。此外，GLYX-13与NR2B特异性拮抗剂（Ro256981）一起治疗未能表现出任何额外的神经保护作用，而NR2A拮抗剂（NVP-AAM007）的应用消除了GLYX-13的神经保护作用，这表明GLYX-13的保护作用应该是通过其对NMDAR亚基成分的调节。我们的研究为 GLYX-13 在缺血中的潜在保护机制提供了重要见解，并提出 NMDAR 的甘氨酸位点作为开发中风中存储突触功能的治疗策略的新靶点。
Excessive activation of NMDA receptors (NMDARs) is implicated in pathological synaptic plasticity also known as post-ischemic long-term potentiation (i-LTP) which was produced by glutamate mediated excitotoxicity after stroke. In the past decades, many NMDARs inhibitors failed in clinical investigations due to severe psychotomimetic side effects. GLYX-13 is a NMDAR modulator with glycine site partial agonist properties and has potential protective effects on ischemic neuronal death. However, the underlying molecular mechanism of GLYX-13 attenuating the ischemic neuronal damage remains elusive. Our study was conducted to examine the molecular, cellular and behavioral actions of GLYX-13 in stroke, and further characterize the mechanism underlying the neuroprotective actions via modulation of the NMDAR subunit composition. In present study we found that in vitro oxygen-glucose deprivation (OGD) stroke model, GLYX-13 blocked i-LTP and restored the ratio of NR2A/NR2B subunit composition. The glycine site of NMDARs full coagonist D-serine completely blocked the effects of GLYX-13 on i-LTP. Besides, in vivo middle cerebral artery occlusion (MCAO) model, GLYX-13 decreased the cerebral infarct volume and reduced injury of hippocampus. Western analysis showed that GLYX-13 down-regulated the expression of phosphorylated NR2B (Tyr1472) and up-regulated phosphorylated NR2A (Tyr1325). Furthermore, GLYX-13 treatment along with NR2B specific antagonist (Ro256981) failed to exhibit any additional neuro-protective effects, whereas the application of NR2A antagonist (NVP-AAM007) abolished the neuroprotective effects of GLYX-13, which suggested that the protective action of GLYX-13 should be by its regulation of NMDAR subunit components. Our study provides important insights on the potential protective mechanism of GLYX-13 in ischemia and proposes the glycine site of NMDARs as a novel target for developing therapeutic strategies to store synaptic function in stroke.