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

Cell Rep Med. 2021 May 18;2(5):100281. doi: 10.1016/j.xcrm.2021.100281.

Abstract

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.

Keywords: CNS drugs; SSRIs; anxiolytics; drug repositioning; fluoxetine; metabolomics; phytosterol; transcriptomics; β-Sitosterol.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Anxiety Agents / pharmacology*
  • Anxiety / drug therapy*
  • Anxiety Disorders / drug therapy*
  • Fear / drug effects
  • Fluoxetine / pharmacology
  • Mice, Inbred C57BL
  • Motor Activity / drug effects
  • Pharmaceutical Preparations / metabolism
  • Prefrontal Cortex / drug effects
  • Proto-Oncogene Proteins c-fos / pharmacology
  • Selective Serotonin Reuptake Inhibitors / pharmacology
  • Sitosterols / pharmacology*
  • Tranquilizing Agents / pharmacology

Substances

  • Anti-Anxiety Agents
  • Pharmaceutical Preparations
  • Proto-Oncogene Proteins c-fos
  • Serotonin Uptake Inhibitors
  • Sitosterols
  • Tranquilizing Agents
  • Fluoxetine
  • gamma-sitosterol