11‐Ethoxyviburtinal improves chronic restraint stress‐induced anxiety‐like behaviors in gender‐specific mice via PI3K/Akt and E₂/ERβ signaling pathways

Abstract

Anxiety disorder is a chronic and disabling psychiatric disorder that is more prevalent in females than in males. 11‐Ethoxyviburtinal is an iridoid extracted from Valeriana jatamansi Jones, which has anxiolytic potential. The aim of the present work was to study the anxiolytic efficacy and mechanism of 11‐ethoxyviburtinal in gender‐specific mice. We first evaluated the anxiolytic‐like efficacy of 11‐ethoxyviburtinal in chronic restraint stress (CRS) mice of different sexes through behavioral experiments and biochemical indexes. In addition, network pharmacology and molecular docking were used to predict potential targets and important pathways for the treatment of anxiety disorder with 11‐ethoxyviburtinal. Finally, the influence of 11‐ethoxyviburtinal on phosphoinositide‐3‐kinase (PI3K)/protein kinase B (Akt) signaling pathway, estrogen receptor β (ERβ) expression, and anxiety‐like behavior in mice was verified by western blotting, immunohistochemistry staining, antagonist intervention methods, and behavioral experiments. 11‐ethoxyviburtinal alleviated the anxiety‐like behaviors induced by CRS and inhibited neurotransmitter dysregulation and HPA axis hyperactivity. It inhibited the abnormal activation of the PI3K/Akt signaling pathway, modulated estrogen production, and promoted ERβ expression in mice. In addition, the female mice may be more sensitive to the pharmacological effects of 11‐ethoxyviburtinal. 11‐ethoxyviburtinal may exert its anxiolytic‐like effects through PI3K/Akt and E2/ERβ signaling pathways. Meanwhile, by comparing the male and female mice, gender differences may affect the therapy and development of anxiety disorder.

Iridoids rich fraction from Valeriana jatamansi Jones promotes axonal regeneration and motor functional recovery after spinal cord injury through activation of the PI3K/Akt signaling pathway

“…For CNS, studies have corroborated that VJJ modulates the hypothalamic–pituitary–adrenal axis ( Yan et al, 2010 ; Shi et al, 2014 ), inhibit microglia activation ( Yang et al, 2022 ), and protect the blood–brain barrier ( Zhang B. et al, 2021 ; Zhang L. et al, 2021 ). Contrary to the findings of this study, VJJ has been previously demonstrated to inhibit rotavirus-induced diarrhoea by suppressing the PI3K/AKT signalling pathway ( Zhang et al, 2021 ), and 11-Ethoxyviburtinal, derived from VJJ, exerts anxiolytic effects through this pathway’s inhibition ( Lyu et al, 2023 ). These variations may stem from the distinct molecular mechanisms underlying various disorders and the diverse bioactive constituents present in VJJ.…”