Yueju pill regulates the mechanism of SIRT1/FoxO3a-mediated autophagy pathway against depression

BACKGROUND In recent years, the identification of novel antidepressants from traditional Chinese medicinal substances has attracted increasing attention. Yueju pill, a compound formula developed by a renowned physician more than 800 years ago, has been shown to alleviate syndromes associated with mood disorders. AIM To explore the regulatory effects of Yueju pill on the SIRT1/FOXO3-mediated autophagy pathway in depression. METHODS Sprague-Dawley rats were randomized into blank, model, fluoxetine (10 mg/kg), and Yueju pill (800 mg/kg) groups. A depression model was established using chronic unpredictable mild stress (CUMS) for 56 days. From day 29, rats in the fluoxetine and Yueju pill groups received intraperitoneal injections of the corresponding drugs once daily for 28 days, while rats in the blank and model groups received equal volumes of normal saline. Depressive-like behaviors were assessed using the sucrose preference test (SPT), forced swimming test (FST), open field test (OFT), and tail suspension test. Serum levels of 5-hydroxytryptamine (5-HT), norepinephrine (NE), dopamine (DA), brain-derived neurotrophic factor (BDNF), and cAMP response element-binding protein (CREB) were measured before and after modeling and treatment. Hippocampal mitochondrial autophagy ultrastructure was examined via transmission electron microscope (TEM). Protein expression of SIRT1/FOXO3a pathway components, LC3, and Beclin-1 in the hippocampus was analyzed using Western blotting. RESULTS Behavioral tests showed that model rats exhibited reduced horizontal and vertical activity in the OFT, reduced sucrose preference in the SPT, and prolonged immobility time in the FST compared with the blank rats. These behavioral impairments were significantly improved in the fluoxetine and Yueju pill groups. TEM results indicated that both treatments alleviated damage to dendrites, dendritic spines, and synaptic ultrastructure of hippocampal neurons. Compared with the model group, fluoxetine and Yueju pill increased DA, 5-HT, and NE levels and upregulated CREB and BDNF protein expression. In addition, LC3-II/LC3-I ratios and the expression levels of SIRT1, and FOXO3a were markedly increased in treated rats while the expression of Beclin-1 was decreased. CONCLUSION Yueju pill effectively alleviates CUMS-induced depressive-like behaviors in rats, possibly related to the promotion of hippocampal neuronal autophagy through the activation of the SIRT1/FoxO3a pathway.