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 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.

 

Comments:

That's an interesting study you've conducted on repurposed drugs for Alzheimer's disease (AD). Identifying potential treatments for such a complex and prevalent condition is crucial. It seems your research aimed to bridge the gap between computational predictions and experimental validation, which is a significant step in drug development.

The discovery of clomiphene citrate and Pik-90 showing inhibition against the BACE1 enzyme in vitro is promising. Since BACE1 is involved in the production of amyloid-beta, a hallmark of AD, inhibiting its activity could potentially slow down disease progression.

Regarding tetrabenazine (TBZ) in the 5XFAD mouse model, while your results did not show a significant effect in behavioral tests or Aβ40 levels, it's important to note the value of negative findings in research. They contribute to our understanding of drug efficacy and potential limitations.

The consideration of sex-stratified results is also significant, as sex differences can play a role in disease progression and treatment response. The fact that this study was among the first to investigate TBZ in a sex-stratified manner in the 5XFAD mouse model could provide valuable insights for future research in this area.

Overall, your findings provide valuable insights into potential candidate drugs for further investigation, particularly clomiphene citrate and Pik-90. Further studies could delve deeper into their mechanisms of action and efficacy in more complex models or clinical trials. Integrating computational methods with experimental validation remains a powerful approach in drug discovery, especially in diseases as complex as Alzheimer's.