Phillyrin Alleviates Memory Impairment in D‐Galactose‐Induced Aged Mice by Suppressing Hippocampal Neuroinflammation via the TLR4 / NF ‐

ABSTRACT

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.