Ferulic acid in Chaihu Shugan San modulates depression-like behavior, endothelial and gastrointestinal dysfunction in rats via the Ghrl-Edn1/Mecp2/P-mTOR/VEGFA pathway: A multi-omics study

Abstract

Ethnopharmacological relevance

In a global context of escalating multimorbidity, characterized by the co-occurrence of major depressive disorder (MDD), endothelial dysfunction (ED), and gastrointestinal dysregulation (GD), the quest for effective treatments has become paramount. Central to these interconnected conditions is oxidative stress (OS), a pivotal factor that has been extensively studied yet remains inadequately addressed. This study introduces Chaihu-Shugan-San (CSS) and its absorbed component ferulic acid (FA), a potent antioxidant derived from medicinal plants, as a novel therapeutic approach with the unique ability to counter the multifaceted effects of acute forced swimming (AFS)-induced depression, ED, and GD. Unlike traditional single-disease-focused studies, our research explores the synergistic effects of CSS and FA across these interrelated disorders, offering a groundbreaking perspective.

Aim of the study

This study aims to evaluate CSS and FA in treating depression-related multimorbidity triggered by AFS and to uncover the shared underlying mechanisms of FA.

Materials and methods

A depression-like model in rats was induced by AFS, and an OS model was established in endothelial cells (ECs) through hydrogen peroxide treatment. We investigated the effects of CSS and FA on MDD, ED, and GD in rats and OS levels in ECs. Our assessments included hematoxylin and eosin (HE) staining, biochemical assays, and behavioral studies. We conducted an integrated analysis of transcriptomics, proteomics, and phosphoproteomics data to elucidate the underlying mechanisms. The identification of relevant targets was confirmed through Western blotting (WB), real-time quantitative polymerase chain reaction (RT-qPCR), molecular docking studies, and an extensive literature review.

Results

Our findings indicate that CSS and FA not only significantly mitigate AFS-induced abnormalities in the open field test (OFT), forced swim test (FST), and related behaviors such as gastric emptying and intestinal transit in rats but also ameliorate depression, ED, GD, inflammation and OS-related biomarker levels, alongside HE staining in gastric sinus and aorta slices. The study also highlights that FA can influence OS and endothelial function in ECs. Moreover, a combined multi-omics analysis unveiled several OS-related pathways, including the mTOR and p53 signaling pathways. Our research elucidates that the Ghrl-Edn1/Mecp2/P-mTOR/Vegfa-associated OS signaling pathway is pivotal in countering AFS-induced multimorbidity, expanding beyond the conventional disease-specific focus.

Conclusions

This pioneering study underscores capability of CSS and FA to tackle AFS-induced multimorbidity concurrently and intricately details FA's antioxidative mechanisms within ECs. The insights gleaned offer a novel perspective on FA's role in multimorbidity regulation and its potential to modulate OS, especially in the complex environment of ECs. Given the urgent global health challenges, our research positions FA as a promising therapeutic contender, advocating for a paradigm shift in multimorbidity management.