Abstract

Chronic stress, a key contributor to neurological disorders, is mechanistically linked to hypothalamic-pituitary-adrenal (HPA) axis dysregulation, neuroinflammation, and hippocampal neuronal apoptosis. Current therapeutic approaches remain limited in efficacy and safety. Schisandrol A, a neuroactive lignan from Schisandra chinensis with superior blood-brain barrier permeability, demonstrates neuroprotective potential. Using a chronic unpredictable mild stress mouse model, this study revealed that schisandrol A administration alleviated anxiety-like behaviors, restored spatial memory, and normalized HPA axis hyperactivity evidenced by reduced serum corticosterone and adrenocorticotropic hormone levels. Mechanistically, schisandrol A promoted glucocorticoid receptor (GR) nuclear translocation, activated CREB/BDNF/TrkB signaling, and suppressed NF-κB-mediated neuroinflammation and apoptosis. In corticosterone-injured hippocampal neurons, schisandrol A enhanced cell viability and GR-dependent transcriptional activity. GR knockdown abolished schisandrol A-mediated BDNF restoration, confirming GR pathway dependency. These findings position schisandrol A as a multitarget modulator bridging neuroendocrine regulation, synaptic plasticity, and antiapoptotic mechanisms, offering therapeutic promise for stress-related neuropsychiatric disorders and supporting its development as a functional food.