Retinoic Acid Ameliorates Chronic Stress-Induced Behavioral Deficits by Modulating Neuroinflammation and Oxidative Stress in Mice Publisher



Azarfarin M ; Hassanzadeh A ; Salatin S ; Asghari KM ; Hamidi S
Source: Gene Reports Published:2026

Abstract

Chronic stress is a significant cause of anxiety and depression, with associated oxidative and inflammatory alterations in the central nervous system. Retinoic acid (RA), a bioactive metabolite of vitamin A, has potential neuroprotective, antioxidant, and anti-inflammatory properties, but its potential use in the treatment of stress-related disorders is largely unexplored. The present study was designed to assess the effects of RA on behavioral, oxidative, and inflammatory outcomes in stress-induced depression and anxiety. In this study, 30 mice were randomly assigned to five groups (n = 6 per group) as follows: normal healthy group (no stress - saline treated), chronic stress group without treatment, chronic stress + vehicle (DMSO), chronic stress + RA (1 mg/kg), chronic stress + RA (2 mg/kg). Chronic stress was induced by daily restraint for 2 h, for a total of 15 days. RA was given intraperitoneally 24 h post-stress. Behavioral outcomes, assessed using the Open Field Test (OFT), Elevated Plus Maze (EPM), and Forced Swim Test (FST), occurred on days 1, 2, and 7 after treatment. After being euthanized, serum cytokines and hormones (TNF-α, IL-1α, IL-10, corticosterone and ACTH) and hippocampal expression of NRF2 and GPx were measured via ELISA and Western blot, respectively. Flow cytometry was performed to quantify the intracellular expression of STAT3, STAT1, NF-κB, malondialdehyde (MDA), and 3-nitrotyrosine (3-NT) in mouse brain tissue. RA lessened behaviors indicating depressive- and anxiety-like outcomes, as shown by decreased immobility in the FST, increased time spent in the open arms in the EPM, and increased activity in the center zone during the OFT. RA also upregulated GPx and NRF2 expression in hippocampal brain tissue, increased IL-10 levels, and decreased corticosterone,ACTH, TNF-α and IL-1α levels. The aforementioned behaviors and molecular effects were dose-dependent whereby the 2 mg/kg dose promoted greater effects, but did not fully normalize behavior or molecular measures. Flow cytometric analysis also revealed a significant reduction in the expression of inflammatory and oxidative stress–related markers in RA-treated mice. In conclusion, retinoic acid ameliorates anxiety- and depressive-like behaviors induced by chronic stress in mice by attenuating HPA axis hyperactivity, suppressing neuroinflammation, and enhancing antioxidant defenses, highlighting its potential as a therapeutic agent for stress-related mood disorders. © 2026 Published by Elsevier Inc.