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

The toxicity of amyloid beta (A beta) 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 A beta 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 A beta(1-40). Importantly, the blockage of NMDAR restored the A beta(1-40)-induced synaptic dysfunction and cognitive impairment. However, LY235959 failed to prevent the inflammatory response associated with A beta(1-40) treatment. Altogether, our data indicate that the acute administration of A beta promotes oxidative stress, a decrease in glutamate transporter expression, and neurotoxicity. Our results reinforce the idea that NMDAR plays a critical regulatory action in A beta toxicity and they provide further pre-clinical evidence for the potential role of the selective and competitive NMDAR antagonists in the treatment of AD. (C) 2011 IBRO. Published by Elsevier Ltd. All rights reserved.