The selective and competitive N-methyl-D-aspartate receptor antagonist, (-)-6-phosphonomethyl-deca-hydroisoquinoline-3-carboxylic acid, prevents synaptic toxicity induced by amyloid-β in mice

Neuroscience. 2011 Sep 29;192:631-41. doi: 10.1016/j.neuroscience.2011.06.038. Epub 2011 Jul 1.

Abstract

The toxicity of amyloid β (Aβ) is highly associated with Alzheimer's disease (AD), which has a high incidence in elderly people worldwide. While the current treatment for moderate and severe AD includes blockage of the N-methyl-d-aspartate receptor (NMDAR), the molecular mechanisms of its effect are still poorly understood. Herein, we report that a single i.p. administration of the selective and competitive (NMDAR) antagonist LY235959 reduced Aβ neurotoxicity by preventing the down-regulation of glial glutamate transporters (glutamate-aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1)), the decrease in glutamate uptake, and the production of reactive oxygen species (ROS) induced by Aβ(1-40). Importantly, the blockage of NMDAR restored the Aβ(1-40)-induced synaptic dysfunction and cognitive impairment. However, LY235959 failed to prevent the inflammatory response associated with Aβ(1-40) treatment. Altogether, our data indicate that the acute administration of Aβ promotes oxidative stress, a decrease in glutamate transporter expression, and neurotoxicity. Our results reinforce the idea that NMDAR plays a critical regulatory action in Aβ toxicity and they provide further pre-clinical evidence for the potential role of the selective and competitive NMDAR antagonists in the treatment of AD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology*
  • Amino Acid Transport System X-AG / drug effects
  • Amino Acid Transport System X-AG / metabolism
  • Amyloid beta-Peptides / toxicity*
  • Animals
  • Disease Models, Animal
  • Excitatory Amino Acid Antagonists / pharmacology*
  • Humans
  • Immunohistochemistry
  • Isoquinolines / pharmacology*
  • Male
  • Mice
  • Reactive Oxygen Species
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Synapses / pathology
  • Synaptophysin / biosynthesis

Substances

  • Amino Acid Transport System X-AG
  • Amyloid beta-Peptides
  • Excitatory Amino Acid Antagonists
  • Isoquinolines
  • Reactive Oxygen Species
  • Receptors, N-Methyl-D-Aspartate
  • Synaptophysin
  • LY 235959