A Novel NMDA Receptor Antagonist Protects against Cognitive Decline Presented by Senescent Mice
A Novel NMDA Receptor Antagonist Protects against Cognitive Decline Presented by Senescent Mice
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DOI：
10.3390/pharmaceutics12030284
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发表时间：
2020-03-01
期刊：
影响因子：
5.4
通讯作者：
Grinan-Ferre, Christian
中科院分区：
文献类型：
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作者：
Companys-Alemany, Julia;Turcu, Andreea L.;Grinan-Ferre, Christian
阿尔茨海默病（AD）是痴呆症的主要原因。非竞争性N-甲基-D-天冬氨酸（NMDA）受体拮抗剂美金刚在临床前治疗后改善了认知和分子改变。然而，临床结果令人沮丧。RL-208是最近描述的一种新的NMDA受体阻滞剂，具有良好的药代动力学特性，在衰老加速小鼠易感8（SAMP 8）（一种迟发型AD（LOAD）小鼠模型）中评价了其体内疗效。口服施用RL-208改善了通过使用三室测试（TCT）、新物体识别测试（NORT）和物体定位测试（奥尔特）评估的认知表现。与行为结果一致，RL-208处理的小鼠组显著改变了NMDAR 2B磷酸化状态水平，但没有改变NMDAR 2A。钙蛋白酶-1和半胱天冬酶-3活性降低，而B细胞淋巴瘤-2（BCL-2）水平增加，表明RL-208处理的SAMP 8中细胞凋亡减少。还在RL-208小鼠中测定了超氧化物歧化酶1（SOD 1）和谷胱甘肽过氧化物酶1（GPX 1）以及过氧化氢（H2 O2）的减少。RL-208处理诱导成熟脑源性神经营养因子（mBDNF）的增加，阻止原肌球蛋白相关激酶B全长（TrkB-FL）裂解，增加突触素（SYN）和突触后密度蛋白95（PSD 95）的蛋白水平。总的来说，这些结果表明突触可塑性的改善。值得注意的是，RL-208还降低了细胞周期蛋白依赖性激酶5（CDK 5）的蛋白水平以及p25/p35比率，表明CDK 5/p25复合物的激酶活性降低。因此，发现了较低水平的过度磷酸化Tau（p-Tau）。总之，这些结果证明了RL-208通过NMDAR阻断的神经保护作用。
Alzheimer's disease (AD) is the leading cause of dementia. Non-competitive N-Methyl-D-aspartate (NMDA) receptor antagonist memantine improved cognition and molecular alterations after preclinical treatment. Nevertheless, clinical results are discouraging. In vivo efficacy of the RL-208, a new NMDA receptor blocker described recently, with favourable pharmacokinetic properties was evaluated in Senescence accelerated mice prone 8 (SAMP8), a mice model of late-onset AD (LOAD). Oral administration of RL-208 improved cognitive performance assessed by using the three chamber test (TCT), novel object recognition test (NORT), and object location test (OLT). Consistent with behavioural results, RL-208 treated-mice groups significantly changed NMDAR2B phosphorylation state levels but not NMDAR2A. Calpain-1 and Caspase-3 activity was reduced, whereas B-cell lymphoma-2 (BCL-2) levels increased, indicating reduced apoptosis in RL-208 treated SAMP8. Superoxide Dismutase 1 (SOD1) and Glutathione Peroxidase 1 (GPX1), as well as a reduction of hydrogen peroxide (H2O2), was also determined in RL-208 mice. RL-208 treatment induced an increase in mature brain-derived neurotrophic factor (mBDNF), prevented Tropomyosin-related kinase B full-length (TrkB-FL) cleavage, increased protein levels of Synaptophysin (SYN) and Postsynaptic density protein 95 (PSD95). In whole, these results point out to an improvement in synaptic plasticity. Remarkably, RL-208 also decreased the protein levels of Cyclin-Dependent Kinase 5 (CDK5), as well as p25/p35 ratio, indicating a reduction in kinase activity of CDK5/p25 complex. Consequently, lower levels of hyperphosphorylated Tau (p-Tau) were found. In sum, these results demonstrate the neuroprotectant role of RL-208 through NMDAR blockade.