Total saponins from

Background: Insomnia is increasingly recognized as a multifactorial disorder characterized by neuroendocrine imbalance, synaptic dysfunction, and impaired energy metabolism, particularly under conditions of chronic stress. Qiye Shen'an Tablets, formulated from total saponins of Methods: Total saponins before (TS-b) and after hydrolysis (TS-a), along with a commercial reference preparation (TS-a+b), were comparatively evaluated in a mouse model of insomnia induced by 4-chloro-DL-phenylalanine (PCPA) combined with systemic stress. Behavioral assessments, hematological analysis, neurotransmitter quantification, histological examination, and metabolomic profiling were conducted. In addition, key pathways associated with the hypothalamic-pituitary-adrenal (HPA) axis and synaptic plasticity were investigated. The neuroprotective effect of notoginsenoside Fd, a major component of TS-a, was further examined in glutamate-injured hippocampal neurons. Results: Compared with TS-b and TS-a+b, TS-a exhibited a more stable composition and superior therapeutic efficacy. It significantly improved sleep-related behaviors, alleviated emotional disturbances, and partially normalized hematological parameters and neurotransmitter levels. Mechanistic analyses indicated that TS-a attenuated dysregulation of HPA axis, mitigated hippocampal glucocorticoid receptor (GR) overactivation, and enhanced the PKA-CREB-BDNF pathway, accompanied by increased expression of synaptic proteins. Metabolomic profiling further suggested the involvement of pathways related to neurotransmission and mitochondrial energy metabolism. Notoginsenoside Fd conferred neuroprotection against glutamate-induced neuronal injury, potentiallythrough modulation of GR signaling. Conclusion: TS-a relieves complex insomnia through coordinated regulation of stress response, synaptic function, and energy metabolism, thereby providing scientific basis for optimizing preparation processes and refining active constituents.