Antidepressant Effects of 20-Glucoginsenoside Rf in an L-AAA-Induced Mouse Model with Glial-Associated Molecular Alterations

Major depressive disorder (MDD) is a leading contributor to disability worldwide, yet current antidepressant treatments remain limited by incomplete remission, treatment resistance, and adverse effects. 20-glucoginsenoside Rf (20-gluco-Rf), a trace bioactive saponin derived from Panax ginseng, has not been sufficiently investigated in depression-related experimental models. In this study, we evaluated the antidepressant potential of 20-gluco-Rf in a mouse model established by prefrontal cortex (PFC) infusion of L-alpha-aminoadipic acid (L-AAA), an astrocyte-selective gliotoxin. Oral administration of 20-gluco-Rf, vehicle, or fluoxetine was initiated before L-AAA infusion into the PFC. 20-Gluco-Rf significantly reduced immobility time in the forced swim and tail suspension tests compared with vehicle treatment. Furthermore, 20-gluco-Rf improved performance in the novel object recognition test. These behavioral changes were accompanied by reduced mRNA expression of proinflammatory mediators, including IL-1β, IL-6, TNF-α, and lipocalin-2, as well as changes in GFAP and IBA-1 protein expression in the PFC. Collectively, these findings provide preliminary in vivo evidence that 20-gluco-Rf is associated with antidepressant-like and cognition-related behavioral effects in an L-AAA-induced mouse model, accompanied by changes in neuroinflammatory and glial-associated molecular markers.