# Baicalin Alleviates Chronic Restraint Stress-Induced Depression-like Behavior by Suppressing ROS/H2O2 Generation via a BDNF-Associated Mechanism in Mice

## TL;DR

Baicalin, a natural compound, shows antidepressant effects in mice by reducing stress-induced depression through antioxidant and BDNF-related mechanisms.

## Contribution

This study reveals a novel mechanism by which baicalin alleviates depression via BDNF–TrkB signaling and antioxidant activity.

## Key findings

- Baicalin produced antidepressant-like effects in mice subjected to chronic restraint stress.
- Baicalin reduced ROS/H2O2 production through a BDNF-associated mechanism.
- Molecular docking showed baicalin binds more effectively to the TrkB receptor than ANA-12.

## Abstract

Major depressive disorder (MDD) is a leading cause of global morbidity and mortality. Although pharmacological treatments are widely used, their effects are often limited, and nearly half of patients show resistance to current antidepressants, including those unresponsive to all available therapies. These challenges highlight the need to better understand the neurobiological mechanisms driving MDD and to develop novel therapeutic strategies, especially those involving natural compounds with multitarget actions. Baicalin, a bioactive flavonoid from Scutellaria baicalensis, exhibits antioxidant, anti-inflammatory, and neuroprotective properties and has recently gained attention for its potential to improve cognitive deficits and mood disorders. In this study, we investigated baicalin’s antidepressant potential and its underlying mechanisms across multiple experimental levels. We found that oral administration of baicalin produced antidepressant-like effects in both naïve mice and those subjected to chronic restraint stress (CRS). CRS impaired hippocampal long-term potentiation (LTP), whereas baicalin restored these synaptic deficits. Importantly, intra-dorsal hippocampal microinjection of the TrkB receptor antagonist ANA-12 abolished baicalin’s antidepressant effects, indicating the involvement of BDNF–TrkB signaling. Baicalin also reduced reactive oxygen species (ROS)/H2O2 production in a BDNF-associated manner, demonstrating clear antioxidant activity. Molecular docking further suggested that baicalin binds more effectively to the TrkB receptor than ANA-12, supporting its capacity to activate TrkB-mediated signaling. By integrating in vivo, ex vivo, in vitro, and in silico approaches, our study shows that baicalin exerts robust antioxidant in vitro and antidepressant effects in vivo. These benefits are primarily mediated through activation of BDNF–TrkB signaling, leading to reduced ROS/H2O2 accumulation and alleviation of CRS-induced depression-like behaviors.