LAUSR

Alzheimer's disease (AD), characterized by impairment of cognitive functions, mainly affects the elderly worldwide. We have previously designed and synthesized a series of memantine nitrate derivatives with vessel dilatory effects. Some of novel compounds have shown 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 GSK3β 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. Furthermore, calcium imaging showed that pretreatment of MN-06 prevented calcium influx through antagonizing the N-methyl-d-aspartate (NMDA) receptor, which has been further confirmed by molecular docking simulation. Preliminary evaluation and prediction in silicon indicated that MN-06 might penetrate the blood brain-barrier. Taken together, MN-06 protected against glutamate-induced excitotoxicity by blocking calcium influx and attenuating PI3-K/Akt/GSK-3β pathway, indicating that MN-06 might be a potential drug for treating dementia.