当前位置: X-MOL 学术Chem. Biol. Interact. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Multifunctional memantine nitrate significantly protects against glutamate-induced excitotoxicity via inhibiting calcium influx and attenuating PI3K/Akt/GSK3beta pathway.
Chemico-Biological Interactions ( IF 5.1 ) Pub Date : 2020-02-21 , DOI: 10.1016/j.cbi.2020.109020
Zheng Liu 1 , Xiaoling Qiu 2 , Shinghung Mak 3 , Baojian Guo 1 , Shengquan Hu 3 , Jiajun Wang 3 , Fangcheng Luo 1 , Daping Xu 3 , Yewei Sun 2 , Gaoxiao Zhang 2 , Guozhen Cui 4 , Yuqiang Wang 2 , Zaijun Zhang 2 , Yifan Han 3
Affiliation  

Overactivation of N-methyl-D-aspartate (NMDA) receptors has been associated with neurodegenerative disorders such as Alzheimer's disease (AD), cerebral vascular disorders and amyotrophic lateral sclerosis (ALS). We have previously designed and synthesized a series of memantine nitrate and some of them have shown vessel dilatory effects and neuroprotective effects; however, the detailed mechanisms have not been elucidated. In this study, we further demonstrated that memantine nitrate-06 (MN-06), one of the novel compounds derived from memantine, possessed significant neuroprotective effects against glutamate-induced excitotoxicity in rat primary cerebellar granule neurons (CGNs). Pretreatment of MN-06 reversed the activation of GSK3b and the suppression of phosphorylated Akt induced by glutamate. In addition, the neuroprotective effects of MN-06 could be abolished by LY294002, the specific phosphatidylinositol 3-kinase (PI3-K) inhibitor. Ca2+ imaging shown that pretreatment of MN-06 prevented Ca2+ influx induced by glutamate. Moreover, MN-06 might inhibit the NMDA-mediated current by antagonizing NDMA receptors, which was further confirmed by molecular docking simulation. Taken together, MN-06 protected against glutamate-induced excitotoxicity by blocking calcium influx and attenuating PI3-K/Akt/GSK-3b pathway, indicating that MN-06 might be a potential drug for treating neurodegenerative disorders.

中文翻译:

多功能硝酸金刚烷胺可通过抑制钙内流并减弱PI3K / Akt / GSK3beta途径来显着保护谷氨酸诱导的兴奋性毒性。

N-甲基-D-天冬氨酸(NMDA)受体的过度活化与神经退行性疾病如阿尔茨海默氏病(AD),脑血管疾病和肌萎缩性侧索硬化(ALS)有关。我们先前已经设计和合成了一系列的硝酸金刚烷胺,其中一些具有血管扩张作用和神经保护作用。然而,尚未阐明详细的机制。在这项研究中,我们进一步证明了硝酸美金刚06(MN-06)是美金刚衍生的新型化合物之一,具有抗谷氨酸诱导的大鼠原发性小脑颗粒神经元(CGNs)兴奋性毒性的显着神经保护作用。MN-06的预处理逆转了GSK3b的激活和谷氨酸诱导的磷酸化Akt的抑制。此外,特异性磷脂酰肌醇3激酶(PI3-K)抑制剂LY294002可以消除MN-06的神经保护作用。Ca2 +成像显示,MN-06的预处理可防止谷氨酸诱导的Ca2 +流入。此外,MN-06可能通过拮抗NDMA受体来抑制NMDA介导的电流,这已通过分子对接模拟得到了进一步证实。两者合计,MN-06通过阻止钙流入并减弱PI3-K / Akt / GSK-3b途径来防止谷氨酸诱导的兴奋性毒性,这表明MN-06可能是治疗神经退行性疾病的潜在药物。MN-06可能通过拮抗NDMA受体来抑制NMDA介导的电流,这已通过分子对接模拟得到了进一步证实。两者合计,MN-06通过阻止钙流入并减弱PI3-K / Akt / GSK-3b途径来保护免受谷氨酸诱导的兴奋性毒性,这表明MN-06可能是治疗神经退行性疾病的潜在药物。MN-06可能通过拮抗NDMA受体来抑制NMDA介导的电流,这已通过分子对接模拟得到了进一步证实。两者合计,MN-06通过阻止钙流入并减弱PI3-K / Akt / GSK-3b途径来防止谷氨酸诱导的兴奋性毒性,这表明MN-06可能是治疗神经退行性疾病的潜在药物。
更新日期:2020-02-21
down
wechat
bug