Forsythoside E alleviates chronic unpredictable mild stress-induced depressive-like behaviors in mice: associations with blood-brain barrier integrity and neuroinflammatory changes in the prefrontal cortex.

RATIONALE: Persistent stress-related depression has increasingly been associated with neuroinflammatory activation and impairment of blood-brain barrier (BBB) function. Forsythoside E (FE), a phenylethanoid glycoside isolated from Forsythia suspensa, is known to exert anti-inflammatory and cytoprotective effects.

OBJECTIVES: Given that its specific role in stress-related depressive states and associated BBB abnormalities remains insufficiently defined, this study aimed to evaluate whether FE could mitigate behavioral impairment and modulate the neurovascular inflammatory microenvironment in a chronic stress model.

METHODS: Male C57BL/6 mice were subjected to chronic unpredictable mild stress (CUMS) for 6 weeks, with FE (50 mg/kg/day) administered orally starting from day 21. Behavioral alterations were evaluated using the sucrose preference, novelty-suppressed feeding, tail suspension, forced swimming, and open-field paradigms. ELISA, immunofluorescence, and Evans blue extravasation were employed to quantify inflammatory changes, BBB leakage, and perivascular IL-17A and VEGFA expression in the prefrontal cortex (PFC).

RESULTS: FE markedly attenuated CUMS-induced behavioral abnormalities, including reduced sucrose preference, prolonged feeding latency, increased immobility, and diminished central exploration, though body weight loss was not significantly corrected. FE treatment was associated with reduced TNF-α, IL-6, IL-1β, and IL-17A levels in the PFC, reduced microglial accumulation, decreased Evans blue extravasation, and reduced perivascular IL-17A and VEGFA expression.

CONCLUSIONS: FE was associated with alleviation of depressive-like behaviors in CUMS-exposed mice. These effects are accompanied by reduced neuroinflammatory responses, decreased BBB permeability, and alterations in IL-17A and VEGFA expression in the prefrontal cortex. These findings suggest a potential involvement of neurovascular and inflammatory processes in the observed effects of FE, although causal mechanisms require further investigation.