title: 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.
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.
authors.affiliation: Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, 88049-900, Florianópolis, Santa Catarina, Brazil.
authors.forename: M A
authors.initials: MA
authors.lastname: Bicca
authors.forename: C P
authors.initials: CP
authors.lastname: Figueiredo
authors.forename: T C
authors.initials: TC
authors.lastname: Piermartiri
authors.forename: F C
authors.initials: FC
authors.lastname: Meotti
authors.forename: Z L
authors.initials: ZL
authors.lastname: Bouzon
authors.forename: C I
authors.initials: CI
authors.lastname: Tasca
authors.forename: R
authors.initials: R
authors.lastname: Medeiros
authors.forename: J B
authors.initials: JB
authors.lastname: Calixto
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D027322:Amino Acid Transport System X-AG / Q000187:drug effects / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D051379:Mice; D017382:Reactive Oxygen Species; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D013569:Synapses / Q000473:pathology; D016708:Synaptophysin / Q000096:biosynthesis
chemical_list: D027322:Amino Acid Transport System X-AG; D016229:Amyloid beta-Peptides; D018691:Excitatory Amino Acid Antagonists; D007546:Isoquinolines; D017382:Reactive Oxygen Species; D016194:Receptors, N-Methyl-D-Aspartate; D016708:Synaptophysin; C088643:LY 235959