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Dose-dependent improvements in learning and memory deficits in APPPS1-21 transgenic mice treated with the orally active Aβ toxicity inhibitor SEN1500.
- Source :
-
Neuropharmacology [Neuropharmacology] 2013 Dec; Vol. 75, pp. 458-66. Date of Electronic Publication: 2013 Sep 10. - Publication Year :
- 2013
-
Abstract
- In the Alzheimer's disease (AD) brain, accumulation of Aβ1-42 peptides is suggested to initiate a cascade of pathological events. To date, no treatments are available that can reverse or delay AD-related symptoms in patients. In the current study, we introduce a new Aβ toxicity inhibitor, SEN1500, which in addition to its block effect on Aβ1-42 toxicity in synaptophysin assays, can be administered orally and cross the blood-brain barrier without adverse effects in mice. In a different set of animals, APPPS1-21 mice were fed with three different doses of SEN1500 (1 mg/kg, 5 mg/kg and 20 mg/kg) for a period of 5 months. Cognition was assessed in a variety of behavioral tests (Morris water maze, social recognition, conditioned taste aversion and passive avoidance). Results suggest a positive effect on cognition with 20 mg/kg SEN1500 compared to control APPPS1-21 mice. However, no changes in soluble or insoluble Aβ1-40 and Aβ1-42 were detected in the brains of SEN1500-fed mice. SEN1500 also attenuated the effect of Aβ1-42 on synaptophysin levels in mouse cortical neurons, which indicated that the compound blocked the synaptic toxicity of Aβ1-42. In vitro and in vivo effects presented here suggest that SEN1500 could be an interesting AD therapeutic.<br /> (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Subjects :
- Administration, Oral
Alzheimer Disease genetics
Amyloid beta-Protein Precursor genetics
Aniline Compounds chemistry
Aniline Compounds pharmacology
Aniline Compounds therapeutic use
Animals
Avoidance Learning drug effects
Disease Models, Animal
Gene Expression Regulation drug effects
Humans
Maze Learning drug effects
Mice
Mice, Transgenic
Mutation genetics
Nitriles chemistry
Presenilin-1 genetics
Pyrimidines administration & dosage
Pyrimidines chemistry
Pyrimidines pharmacology
Pyrimidines therapeutic use
Synaptophysin metabolism
Taste drug effects
Alzheimer Disease complications
Amyloid beta-Peptides antagonists & inhibitors
Learning Disabilities drug therapy
Learning Disabilities etiology
Memory Disorders etiology
Nitriles administration & dosage
Peptide Fragments antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1873-7064
- Volume :
- 75
- Database :
- MEDLINE
- Journal :
- Neuropharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 24035915
- Full Text :
- https://doi.org/10.1016/j.neuropharm.2013.08.030