Multifunctional memantine nitrate significantly protects against glutamate-induced excitotoxicity via inhibiting calcium influx and attenuating PI3K/Akt/GSK3beta pathway

Chem Biol Interact. 2020 Jul 1:325:109020. doi: 10.1016/j.cbi.2020.109020. Epub 2020 Feb 21.

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. 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.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Biological Transport / drug effects
  • Calcium / metabolism*
  • Cell Count
  • Cerebellum / cytology
  • Glutamic Acid / toxicity*
  • Glycogen Synthase Kinase 3 beta / metabolism*
  • Hippocampus / cytology
  • Memantine / metabolism
  • Memantine / pharmacology*
  • Molecular Docking Simulation
  • Neurons / cytology
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neuroprotective Agents / metabolism
  • Neuroprotective Agents / pharmacology
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Protein Conformation
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / chemistry
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Signal Transduction / drug effects

Substances

  • Neuroprotective Agents
  • Receptors, N-Methyl-D-Aspartate
  • Glutamic Acid
  • Glycogen Synthase Kinase 3 beta
  • Proto-Oncogene Proteins c-akt
  • Calcium
  • Memantine