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

Nicolas Panayotis (1) , Philip A Freund (1) , Letizia Marvaldi (1) , Tali Shalit (1) , Alexander Brandis (1) , Tevie Mehlman (1) , Michael M Tsoory (1) , Mike Fainzilber (1)

1 Weizmann Institute of Science [Rehovot, Israël]

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 alpha5 mutant mouse model with reduced anxiety identifies the hypocholesterolemic agent beta-sitosterol as a promising candidate. Beta-sitosterol activity is validated by both intraperitoneal and oral application in mice, revealing it as the only clear anxiolytic from five closely related phytosterols. Beta-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 beta-sitosterol with the SSRI fluoxetine. These preclinical findings support further development of beta-sitosterol, either as a standalone anxiolytic or in combination with low-dose SSRIs.

Domaines: Neurobiologie; Pharmacologie; Bio-Informatique, Biologie Systémique [q-bio.QM]

Nicolas Panayotis, Philip A Freund, Letizia Marvaldi, Tali Shalit, Alexander Brandis, et al.. β-sitosterol reduces anxiety and synergizes with established anxiolytic drugs in mice. Cell Reports Medicine, 2021, 2 (5), pp.100281. ⟨10.1016/j.xcrm.2021.100281⟩. ⟨hal-03523050⟩