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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
- Source :
- Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual), Universidade de São Paulo (USP), instacron:USP
- Publication Year :
- 2011
-
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.
- Subjects :
- Male
medicine.drug_class
Amino Acid Transport System X-AG
Synaptophysin
Pharmacology
medicine.disease_cause
Receptors, N-Methyl-D-Aspartate
GLUTAMATOS
Mice
Alzheimer Disease
medicine
Animals
Humans
Receptor
Amyloid beta-Peptides
Chemistry
General Neuroscience
Glutamate receptor
Antagonist
Neurotoxicity
medicine.disease
Receptor antagonist
Isoquinolines
Immunohistochemistry
Disease Models, Animal
Biochemistry
Synapses
NMDA receptor
Alzheimer's disease
Reactive Oxygen Species
Excitatory Amino Acid Antagonists
Oxidative stress
Subjects
Details
- ISSN :
- 18737544
- Volume :
- 192
- Database :
- OpenAIRE
- Journal :
- Neuroscience
- Accession number :
- edsair.doi.dedup.....cf031a5f165b581bb0694bebc1240bc0