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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 :
-
Neuroscience [Neuroscience] 2011 Sep 29; Vol. 192, pp. 631-41. Date of Electronic Publication: 2011 Jul 01. - Publication Year :
- 2011
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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.<br /> (Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.)
- Subjects :
- Amino Acid Transport System X-AG drug effects
Amino Acid Transport System X-AG metabolism
Animals
Disease Models, Animal
Humans
Immunohistochemistry
Male
Mice
Reactive Oxygen Species
Receptors, N-Methyl-D-Aspartate antagonists & inhibitors
Synapses pathology
Synaptophysin biosynthesis
Alzheimer Disease metabolism
Alzheimer Disease pathology
Amyloid beta-Peptides toxicity
Excitatory Amino Acid Antagonists pharmacology
Isoquinolines pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1873-7544
- Volume :
- 192
- Database :
- MEDLINE
- Journal :
- Neuroscience
- Publication Type :
- Academic Journal
- Accession number :
- 21756976
- Full Text :
- https://doi.org/10.1016/j.neuroscience.2011.06.038