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β-sitosterol reduces anxiety and synergizes with established anxiolytic drugs in mice

Anxiety and stress-related conditions represent a significant health burden in modern society. Unfortunately, most anxiolytic drugs are prone to side effects, limiting their long-term usage. Here, we employ a bioinformatics screen to identify drugs for repurposing as anxiolytics. Comparison of drug-...

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Autores principales: Panayotis, Nicolas, Freund, Philip A., Marvaldi, Letizia, Shalit, Tali, Brandis, Alexander, Mehlman, Tevie, Tsoory, Michael M., Fainzilber, Mike
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8149471/
https://www.ncbi.nlm.nih.gov/pubmed/34095883
http://dx.doi.org/10.1016/j.xcrm.2021.100281
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author Panayotis, Nicolas
Freund, Philip A.
Marvaldi, Letizia
Shalit, Tali
Brandis, Alexander
Mehlman, Tevie
Tsoory, Michael M.
Fainzilber, Mike
author_facet Panayotis, Nicolas
Freund, Philip A.
Marvaldi, Letizia
Shalit, Tali
Brandis, Alexander
Mehlman, Tevie
Tsoory, Michael M.
Fainzilber, Mike
author_sort Panayotis, Nicolas
collection PubMed
description Anxiety and stress-related conditions represent a significant health burden in modern society. Unfortunately, most anxiolytic drugs are prone to side effects, limiting their long-term usage. Here, we employ a bioinformatics screen to identify drugs for repurposing as anxiolytics. Comparison of drug-induced gene-expression profiles with the hippocampal transcriptome of an importin α5 mutant mouse model with reduced anxiety identifies the hypocholesterolemic agent β-sitosterol as a promising candidate. β-sitosterol activity is validated by both intraperitoneal and oral application in mice, revealing it as the only clear anxiolytic from five closely related phytosterols. β-sitosterol injection reduces the effects of restraint stress, contextual fear memory, and c-Fos activation in the prefrontal cortex and dentate gyrus. Moreover, synergistic anxiolysis is observed when combining sub-efficacious doses of β-sitosterol with the SSRI fluoxetine. These preclinical findings support further development of β-sitosterol, either as a standalone anxiolytic or in combination with low-dose SSRIs.
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spelling pubmed-81494712021-06-03 β-sitosterol reduces anxiety and synergizes with established anxiolytic drugs in mice Panayotis, Nicolas Freund, Philip A. Marvaldi, Letizia Shalit, Tali Brandis, Alexander Mehlman, Tevie Tsoory, Michael M. Fainzilber, Mike Cell Rep Med Report Anxiety and stress-related conditions represent a significant health burden in modern society. Unfortunately, most anxiolytic drugs are prone to side effects, limiting their long-term usage. Here, we employ a bioinformatics screen to identify drugs for repurposing as anxiolytics. Comparison of drug-induced gene-expression profiles with the hippocampal transcriptome of an importin α5 mutant mouse model with reduced anxiety identifies the hypocholesterolemic agent β-sitosterol as a promising candidate. β-sitosterol activity is validated by both intraperitoneal and oral application in mice, revealing it as the only clear anxiolytic from five closely related phytosterols. β-sitosterol injection reduces the effects of restraint stress, contextual fear memory, and c-Fos activation in the prefrontal cortex and dentate gyrus. Moreover, synergistic anxiolysis is observed when combining sub-efficacious doses of β-sitosterol with the SSRI fluoxetine. These preclinical findings support further development of β-sitosterol, either as a standalone anxiolytic or in combination with low-dose SSRIs. Elsevier 2021-05-18 /pmc/articles/PMC8149471/ /pubmed/34095883 http://dx.doi.org/10.1016/j.xcrm.2021.100281 Text en © 2021 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Report
Panayotis, Nicolas
Freund, Philip A.
Marvaldi, Letizia
Shalit, Tali
Brandis, Alexander
Mehlman, Tevie
Tsoory, Michael M.
Fainzilber, Mike
β-sitosterol reduces anxiety and synergizes with established anxiolytic drugs in mice
title β-sitosterol reduces anxiety and synergizes with established anxiolytic drugs in mice
title_full β-sitosterol reduces anxiety and synergizes with established anxiolytic drugs in mice
title_fullStr β-sitosterol reduces anxiety and synergizes with established anxiolytic drugs in mice
title_full_unstemmed β-sitosterol reduces anxiety and synergizes with established anxiolytic drugs in mice
title_short β-sitosterol reduces anxiety and synergizes with established anxiolytic drugs in mice
title_sort β-sitosterol reduces anxiety and synergizes with established anxiolytic drugs in mice
topic Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8149471/
https://www.ncbi.nlm.nih.gov/pubmed/34095883
http://dx.doi.org/10.1016/j.xcrm.2021.100281
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