Preliminary In Vitro and In Vivo Insights of In Silico Candidate Repurposed Drugs for Alzheimer's Disease

Alzheimer's disease (AD) is a progressive neurodegenerative disease and is the most common type of dementia. Although a considerably large amount of money has been invested in drug development for AD, no disease modifying treatment has been detected so far. In our previous work, we developed a...

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Published in:Life (Basel, Switzerland) Switzerland), 2023-04, Vol.13 (5), p.1095
Main Authors: Savva, Kyriaki, Zachariou, Margarita, Kynigopoulos, Demos, Fella, Eleni, Vitali, Maria-Ioanna, Kosofidou, Xeni, Spyrou, Michail, Sargiannidou, Irene, Panayiotou, Elena, Dietis, Nikolas, Spyrou, George M
Format: Article
Language:English
Subjects:
Alzheimer's disease
Chemical compounds
Clinical trials
Clomiphene
Computational neuroscience
Dementia disorders
Drug development
Drug discovery
Drug therapy
Drugs
Enzyme-linked immunosorbent assay
Enzymes
Immunoassay
in silico drug repurposing
in vitro testing
In vivo methods and tests
in vivo testing
Mutation
Nervous system agents
Neurodegeneration
Neurodegenerative diseases
Pharmaceutical research
Pharmacokinetics
Proteins
Statistical analysis
Tetrabenazine
β-Site APP-cleaving enzyme 1
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Summary:Alzheimer's disease (AD) is a progressive neurodegenerative disease and is the most common type of dementia. Although a considerably large amount of money has been invested in drug development for AD, no disease modifying treatment has been detected so far. In our previous work, we developed a computational method to highlight stage-specific candidate repurposed drugs against AD. In this study, we tested the effect of the top 13 candidate repurposed drugs that we proposed in our previous work in a severity stage-specific manner using an in vitro BACE1 assay and the effect of a top-ranked drug from the list of our previous work, tetrabenazine (TBZ), in the 5XFAD as an AD mouse model. From our in vitro screening, we detected 2 compounds (clomiphene citrate and Pik-90) that showed statistically significant inhibition against the activity of the BACE1 enzyme. The administration of TBZ at the selected dose and therapeutic regimen in 5XFAD in male and female mice showed no significant effect in behavioral tests using the Y-maze and the ELISA immunoassay of Aβ40. To our knowledge, this is the first time the drug tetrabenazine has been tested in the 5XFAD mouse model of AD in a sex-stratified manner. Our results highlight 2 drugs (clomiphene citrate and Pik-90) from our previous computational work for further investigation.
ISSN:2075-1729
2075-1729
DOI:10.3390/life13051095