What type of study is this?

This is a Animal Study study (also classified as: Observational).

August 20, 2025Open Access

Yokukansan Ameliorates Depression-like Behavior Induced by Chronic Unpredictable Mild Stress in Rats by Regulating Neuroinflammation and Neurotrophins through Modulating Phosphoinositide 3-Kinase/Protein Kinase B/Glycogen Synthase Kinase 3 Beta Pathway

Key Points

Yokukansan effectively improved depressive behavior in rats under chronic unpredictable mild stress, showing significant behavioral changes.
The treatment notably increased sucrose preference and reduced immobility in forced swim tests, with p-values less than 0.01.
Assessment utilized a chronic mild stress model over six weeks, alongside multiple behavioral and biochemical tests for validation.
Yokukansan's effects suggest significant involvement of the PI3K/Akt/GSK3 beta pathway in restoring neurotransmitter levels and reducing inflammation.

Abstract

Abstract Objective: Yokukansan (YKS) is a traditional formula for neurological conditions, effectively addressing anxiety and depression symptoms. This study aims to investigate the antidepressant effects of YKS on chronic unpredictable mild stress (CUMS)-induced depressive-like behavior in rats, focusing on the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/glycogen synthase kinase 3 beta (GSK3 β) pathway. Materials and Methods: Rats underwent the 6 weeks-CUMS model; YKS was administered at three doses in the last 2 weeks; Fluoxetine-positive control. Depressive behaviors are assessed using the open field test, forced swim test (FST), and sucrose preference test. Neurotrophic factors (brain-derived neurotrophic factor BDNF and nerve growth factor NGF), inflammatory cytokines (tumor necrosis factor alpha TNF-α, interleukin-6 IL-6, IL-1 β, and IL-10), neurotransmitters (5-hydroxytryptamine 5-HT, dopamine, and gamma-aminobutyric acid), and cortisol were measured. The PI3K/Akt/GSK3 β pathway was analyzed by Western blot and validated by a code for a compound that inhibits AKT (MK-2206). Neuronal integrity in the hippocampus and astrocyte/microglial activation were examined with Nissl staining and immunohistochemistry. Results: Results are expressed as means ± standard error of the mean one-way analysis of variance was used, with P < 0.05 considered significant. YKS improved depressive-behavior in CUMS rats by increasing sucrose preference ( P < 0.01) and reduced FST immobility ( P < 0.01). YKS restored BDNF and NGF levels ( P < 0.05), reduced TNF-α ( P < 0.01), IL-6, and IL-1β ( P < 0.05), raised 5-HT ( P < 0.05), dopamine ( P < 0.0001), decreased cortisol ( P < 0.001), and improved astrocyte/microglial activation. YKS-activated PI3K/Akt/GSK3 β signaling increased p-Akt and p-GSK3 β ( P < 0.05); effects were blocked by MK-2206 ( P < 0.01). Conclusions: YKS shows antidepressant potential by boosting BDNF and NGF, reducing pro-inflammatory cytokines, and protecting neurons via the PI3K/Akt/GSK3 β pathway. It restores neurotransmitters, lowers cortisol, and alleviates stress, supporting YKS as a therapy for depression.

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