Daidzein Prevents Stress-Induced Synaptic Plasticity Impairment and Behavioral Dysfunction via ERK/CREB/BDNF Signaling Pathway

Chronic stress (CS) represents a pivotal environmental trigger for depression. It induces depression-like behaviors primarily by disrupting hypothalamic–pituitary–adrenal (HPA) axis homeostasis and impairing hippocampal synaptic plasticity. Flavonoids are abundant in human diet and possess significant neuroprotective potential. We screened a library of 339 flavonoid compounds. Daidzein (DAI) was identified as the lead compound. Subsequently, in rats subjected to chronic restraint stress (CRS), DAI administration effectively ameliorated depression-like behaviors, and attenuated hippocampal histopathological damage. Network pharmacology and molecular docking analyses suggested that ERK-related signaling may be involved in the protective effects of DAI, and molecular dynamics simulations supported the stability of the DAI-ERK2 complex. Furthermore, DAI activated the ERK/CREB/BDNF signaling cascade, an effect that was partially reversed by ERK inhibitor intervention. Notably, DAI also enhanced dendritic complexity and spine density in hippocampus. In summary, our study demonstrates that DAI alleviates stress-induced synaptic plasticity damage through the ERK/CREB/BDNF signaling pathway.