Fermented Suan Zao Ren ameliorates sleep in a mouse model of blood-deficiency insomnia by modulating hippocampal monoamines

Objective: To investigate the pharmacodynamic effects of Ziziphus jujuba Mill. var. spinosa (Bunge) Hu ex H. F. Chou (Z. jujuba, Suan Zao Ren) fermented with the fungus of Poria cocos (Schw.) Wolf (P. cocos strain) and Massa Medicata Fermentata (MMF) on hippocampal monoamine neurotransmitters in mice with blood-deficiency insomnia. Methods: Fermented Z. jujuba products were prepared from P. cocos strain (PCS) and MMF. A mouse model of blood-deficiency insomnia was established via intraperitoneal injection of cyclophosphamide and p-chlorophenylalanine. Model evaluation included general physical status, a pentobarbital sodium-induced sleep test, and peripheral blood analysis, including white blood cells, red blood cells (RBC), and hemoglobin (Hb). Hippocampal levels of norepinephrine (NE), dopamine (DA), 5-hydroxytryptamine (5-HT), and 5-hydroxyindoleacetic acid (5-HIAA) were measured using high-performance liquid chromatography with electrochemical detection. Results: Compared to the control group, mice in the model group exhibited shortened sleep duration (P = .003), decreased RBC and Hb levels (P = .005 and P = .008, respectively), confirming successful modeling. In the hippocampal tissue of model mice, the levels of NE, 5-HT, and 5-HIAA were significantly decreased (all P < .05), whereas DA levels were significantly increased (P = .024). Treatment with fermented Z. jujuba significantly prolonged sleep duration (both P < .01). Moreover, The PCS group had significantly higher hippocampal NE, 5-HT, and 5-HIAA levels (all P < .01). The MMF group showed increased 5-HT and 5-HIAA (P = .040 and P = .0085) but decreased DA (P = .033). Additionally, NE was significantly lower in the MMF group than in the PCS group (P = .008). Conclusion: Fermented Z. jujuba products effectively ameliorated sleep disorders in mice with blood-deficiency insomnia. These pharmacological effects may relate to the targeted remodeling of monoamine neurotransmitter homeostasis in the hippocampus, specifically by upregulating NE, 5-HT, and 5-HIAA levels and downregulating DA levels.