Tripchlorolide improves age-associated cognitive deficits by reversing hippocampal synaptic plasticity impairment and NMDA receptor dysfunction in SAMP8 mice
Tripchlorolide improves age-associated cognitive deficits by reversing hippocampal synaptic plasticity impairment and NMDA receptor dysfunction in SAMP8 mice
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三氯内酯通过逆转 SAMP8 小鼠海马突触可塑性损伤和 NMDA 受体功能障碍，改善与年龄相关的认知缺陷
DOI：
10.1016/j.bbr.2013.10.010
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发表时间：
2014-01-01
影响因子：
2.7
通讯作者：
Chen, Xiao-chun
中科院分区：
文献类型：
--
作者：
Lin, Nan;Pan, Xiao-dong;Chen, Xiao-chun
阿尔茨海默病(AD)等与年龄相关的神经退行性疾病伴发的认知和行为缺陷与突触可塑性受损密切相关。在此，我们利用衰老加速P8(SAMP8)的小鼠模型，报道了雷公藤多酚(T-4)通过N-甲基-n-天冬氨酸受体(NMDAR)依赖的信号通路改善认知障碍和促进海马片长时程增强(LTP)的作用。结果表明，长期给予低剂量T-4(每天0.25、1.0或4.0微克/公斤，连续75天腹腔注射)可显著改善老年SAMP8小鼠的学习记忆功能，包括Y迷宫和Morris水迷宫。此外，T-4还以剂量依赖的方式逆转SAMP8小鼠海马CA1区LTP的损伤。此外，它还上调了海马区磷酸化NMDAR1、突触后密度-95(PSD-95)、磷酸化钙钙调素依赖激酶II(CaMKII)、磷酸化CREB和脑源性神经营养因子(BDNF)的水平。这表明T-4可以预防NMDAR介导的突触可塑性相关信号分子的损伤。在最佳剂量下，T-4对小鼠的血细胞计数、血液生化指标或存活率没有明显的副作用。这种逆转年龄相关性突触功能障碍和NMDAR功能缺陷的新机制表明，T-4可以阻止AD的一个关键早期事件的出现。以SAMP8小鼠为模型开发AD治疗干预措施，为雷公藤内酯治疗AD的临床应用提供了新的视角。(C)2013爱思唯尔B.V.保留所有权利。
Deficits in cognition and performance accompanying age-related neurodegenerative diseases such as Alzheimer's disease (AD) are closely associated with the impairment of synaptic plasticity. Here, using a mouse model of senescence-accelerated P8 (SAMP8), we reported the role of tripchlorolide (T-4), an extract of the natural herb Tripterygium wilfordii Hook F, in improving cognitive deficits and promoting the long-term potentiation (LTP) of hippocampal slices via the N-methyl-n-aspartate receptor (NMDAR)dependent signaling pathway. Our results demonstrated that chronic administration of T-4 at low doses (0.25, 1.0, or 4.0 mu g/kg per day, injected intraperitoneally for 75 days) significantly improved learning and memory function in aged SAMP8 mice, as indicated by a chain of behavioral tests including the Y-maze and Morris water maze. Additionally, T-4 reversed the impaired LTP in hippocampal CA1 regions of SAMP8 mice in a dose-dependent manner. Moreover, it upregulated the levels of phospho-NMDAR1, postsynaptic density-95 (PSD-95), phospho-calcium-calmodulin dependent kinase II (CaMKII), phospho-CREB and brain derived neurotrophic factor (BDNF) in the hippocampus. This indicates that T-4 prevents the impairment of NMDAR-mediated synaptic plasticity-related signal molecules. At optimal doses, T-4 did not show significant side-effects on blood counts, blood biochemical measures, or survival of the mice. This novel mechanism in reversing age-related synaptic dysfunction and NMDAR functional deficits suggests that T-4 can halt the manifestation of a key early-stage event in AD. With the consideration of SAMP8 mice as a model to develop therapeutic interventions for AD, our findings provide new insight into the clinical application of tripchlorolide in AD treatment. (C) 2013 Elsevier B.V. All rights reserved.