Short-term stress is known to trigger oxidative and neuroinflammatory responses that contribute to the onset and progression of major depressive disorder (MDD). Phenolic compounds, such as grape seed extract (GSE), have gained attention for their ability to modulate these biological pathways. This study aimed to evaluate whether GSE (20 or 40 mg/kg, oral route) exerts antidepressant-like effects and mitigates stress-induced biochemical alterations in female mice exposed to the acute restraint stress (ARS) model. Female mice were pretreated with GSE and subsequently subjected to ARS. Behavioral outcomes were assessed using the tail suspension test (TST) and open field test (OFT). Plasma corticosterone levels, reactive species (RS) production in the prefrontal cortex, hippocampi, and small intestine, and mRNA expression of inflammatory mediators (NF-κB, IL-1β, IFN-γ) in brain and gut tissues were quantified through standard biochemical and molecular analyses. GSE pretreatment significantly prevented the ARS-induced increase in immobility time in the TST, without affecting locomotor activity in the OFT. ARS exposure elevated corticosterone concentrations and RS generation across central and peripheral tissues; both effects were attenuated by GSE. Additionally, GSE downregulated stress-induced expression of pro-inflammatory cytokines in neural and intestinal samples, indicating suppression of key inflammatory pathways. These findings demonstrate that GSE exerts antidepressant-like, antioxidant, and anti-inflammatory effects through interconnected redox and cytokine signaling pathways, as summarized in the Graphical Abstract. Importantly, this study provides novel evidence that GSE acts along the gut-brain axis, mitigating corticosterone-driven oxidative and inflammatory responses. These results highlight GSE as a promising natural compound for the prevention and management of stress-related neuropsychiatric disorders.
