Multifunctional memantine nitrate significantly protects against glutamate-induced excitotoxicity via inhibiting calcium influx and attenuating PI3K/Akt/GSK3beta pathway
Zheng Liu, Xiaoling Qiu, Shinghung Mak, Baojian Guo, Shengquan Hu, Jiajun Wang, Fangcheng Luo, Daping Xu, Yewei Sun, Gaoxiao Zhang, Guozhen Cui, Yuqiang Wang, Zaijun Zhang, Yifan Han, Yifan Han
Abstract
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. Ca 2+ imaging shown that pretreatment of MN-06 prevented Ca 2+ 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.