Total saponins from Panax notoginseng leaves alleviate complex insomnia by modulating neuroendocrine function, synaptic plasticity, and energy metabolism.

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 Panax notoginseng leaves (PNL), are widely used in clinical practice, however, their active constituents and underlying mechanisms remain incompletely understood. Notably, partial hydrolysis of saponins during the preparation process may modify their chemical composition, thereby potentially influencing therapeutic efficacy. 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.