3-O-p-coumaroylquinic acid and 4-O-p-coumaroylquinic acid from Hemerocallis citrina Baroni exert antidepressant effects via CA/Dopa/DA/NE and PKA/CREB/BDNF signaling pathways.

The ancient text "Compendium of Materia Medica" records that Hemerocallis citrina Baroni (daylily) was used for antidepressant, but its active components and mechanisms remain unknown. In this study, the H. citrina extract was initially fractionated into three parts, and only the 35% HCW (35% ethanol-eluted fraction of Hemerocallis citrina water extract, LILYANTIDEPRES®) demonstrated significant antidepressant activity, notably increasing the levels of dopamine (DA), norepinephrine (NE), and brain-derived neurotrophic factor (BDNF) in the brain of depressed mice. It's also significantly reducing the IL-6 (Interleukin-6) and MDA (Malondialdehyde) levels, and improving the gut microbiota. The main components of the 35% HCW were identified as 3-O-p-coumaroylquinic acid (1) and 4-O-p-coumaroylquinic acid (2), which were also chemically synthesized. Both compounds exhibited significant antidepressant activity by increasing the levels of DA, NE, and BDNF in the brain of depressed mice and significantly reducing the levels of IL-6 and TNF-α (Tumor Necrosis Factor-α). A potential mechanism to elevate DA and NE levels in the depressed mice brain via the CA (coumaroylquinic acid)/Dopa/DA/NE pathway. Additionally, compounds 1 and 2 significantly increase BDNF levels through the PKA (Protein Kinase A)/CREB (cAMP Response Element-Binding Protein)/BDNF signaling pathway. This study provides the first elucidation of the antidepressant components of H. citrina and the mechanisms, laying the foundation for the development of antidepressant products and the high-value utilization of H. citrina resources.