Total saponins from Panax notoginseng leaves alleviate composite insomnia by regulating neuroendocrine function, synaptic plasticity, and energy metabolism

Background Insomnia is increasingly recognized as a complex disorder involving neuroendocrine imbalance, synaptic dysfunction, and disrupted energy metabolism, especially under chronic stress. Qiye Shen’an Tablets, prepared from total saponins of Panax notoginseng leaves (PNL), are widely used in clinical practice, but their active composition and mechanisms are not fully understood. During preparation, partial hydrolysis of saponins may alter their chemical profile and consequently affect efficacy. Methods Total saponins before (TS-b) and after hydrolysis (TS-a), along with a commercial reference (TS-a+b), were compared using a mouse model of insomnia induced by 4-chloro-DL-phenylalanine (PCPA) combined with systemic stress. Behavioral evaluation, blood analysis, neurotransmitter measurement, histological observation, and metabolomic profiling were performed. In addition, key pathways associated with the hypothalamic–pituitary–adrenal (HPA) axis and synaptic plasticity were analyzed. The effect of Notoginsenoside Fd was further tested in glutamate-injured hippocampal neurons. Results Compared with TS-b and TS-a+b, TS-a showed a more stable composition and better therapeutic effects. It improved sleep-related behaviors, alleviated emotional disturbances, and partially corrected hematological and neurotransmitter changes. Further analysis suggested that TS-a attenuated HPA axis dysregulation, modulated hippocampal glucocorticoid receptor (GR) overactivation, and enhanced the PKA–CREB–BDNF pathway along with synaptic protein expression. Metabolomics indicated involvement of neurotransmission and mitochondrial energy metabolism. Notoginsenoside Fd also protected neurons from glutamate-induced damage, potentially involving the modulation of GR signaling. Conclusion TS-a relieves complex insomnia through combined regulation of stress response, synaptic function, and energy metabolism, providing support for optimizing preparation processes and active components.