Phillyrin Alleviates Memory Impairment in D-Galactose-Induced Aged Mice by Suppressing Hippocampal Neuroinflammation via the TLR4/NF-κB Signaling Pathway.

Phillyrin (PHI), a major dietary lignan derived from Forsythia suspensa, is a neuroprotective bioactive compound. This study investigated the protective effects of PHI against D-galactose (D-gal)-induced memory decline in mice and explored the underlying mechanisms, focusing on neuroinflammation mediated by Toll-like receptor 4 (TLR4) and nuclear factor kappa B (NF-κB). In vivo, mice were assigned to control, D-gal, and PHI treatment groups. Behavioral performance, hippocampal histopathology, oxidative stress, inflammatory markers, and related protein expression were evaluated. In vitro, HT22 cells exposed to D-gal were treated with PHI, TAK-242, or both, and analyzed for TLR4/NF-κB proteins by Western blotting (WB). PHI attenuated cognitive impairment, reduced neuroinflammation, and preserved synaptic structure. Moreover, PHI downregulated TLR4, p-IκBα, and p-NF-κB expression both in hippocampal tissue and HT22 cells, consistent with the effects of the TLR4 inhibitor TAK-242. These findings suggest that PHI exerts neuroprotective and anti-inflammatory effects via TLR4/NF-κB modulation, highlighting its potential as a dietary bioactive compound to support cognitive health during aging.