Shenghui decoction improves sleep-deprivation-induced cognitive impairment in mice by modulating neuroinflammation, NRG1/ErbB4 signaling, and purine metabolism.

ETHNOPHARMACOLOGICAL RELEVANCE: Shenghui Decoction (SHD) is a traditional Chinese medicine formula first documented by Chen Shiduo in Bian Zheng Lu during the Qing dynasty. It has traditionally been used for disorders related to forgetfulness, insomnia, and mental disturbance. Cognitive impairment induced by sleep deprivation (SD) shares features with these traditional indications. However, the mechanisms underlying the protective effects of SHD against SD-induced cognitive impairment remain unclear.

OBJECTIVE: This study aimed to evaluate the protective effects of SHD against SD-induced cognitive impairment in mice and investigate potential mechanisms involving neuroinflammation, NRG1/ErbB4-related synaptic plasticity, and metabolic homeostasis.

MATERIALS AND METHODS: Male C57BL/6 mice were randomly assigned to five groups: the negative control group (Control), SD model group (Model), melatonin group (MT, 100 mg/kg), low-dose SHD group (SHD-L, 13.5 g/kg), and high-dose SHD group (SHD-H, 27 g/kg). Mice received intragastric treatment once daily for 21 consecutive days, and 72-h SD was initiated on day 18 using a modified multiple-platform water-environment method. Cognitive function was evaluated using the novel object recognition test and Morris water maze. Hippocampal histopathology was assessed by hematoxylin and eosin and Nissl staining. Western blotting was used to quantify hippocampal levels of interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), NRG1, ErbB4, phosphorylated ErbB4 (p-ErbB4), parvalbumin (PV), postsynaptic density protein 95 (PSD95), and brain-derived neurotrophic factor (BDNF). Network pharmacology analysis was performed using the 15 blood-absorbed prototype constituents of SHD identified in our previous study. Untargeted serum metabolomics was subsequently conducted using ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry. Finally, network pharmacology and metabolomics data were integrated for joint analysis.

RESULTS: SD significantly impaired recognition and spatial learning and memory. These behavioral deficits were accompanied by marked histopathological changes in the hippocampal dentate gyrus and cornu ammonis 3 regions. SHD-H significantly ameliorated both the behavioral and histopathological abnormalities. SD also increased hippocampal IL-1β, IL-6, and TNF-α levels, while reducing NRG1, PV, PSD95, and BDNF levels and the p-ErbB4/ErbB4 ratio. SHD-H reversed these changes to varying degrees. Network pharmacology identified 88 core targets. Kyoto Encyclopedia of Genes and Genomes enrichment analysis highlighted Ras signaling pathways, PI3K-Akt signaling pathways, MAPK signaling pathways, and ErbB signaling pathways. Untargeted serum metabolomics identified 48 differential metabolites altered by SD. Pathway enrichment analysis showed that these metabolites were mainly associated with glycerophospholipid metabolism, sphingolipid metabolism, and purine metabolism. SHD-H shifted these metabolic alterations toward the Control profile to varying degrees. A MetScape-based metabolite-reaction-enzyme-gene network was constructed to identify genes associated with the 48 differential metabolites. Intersecting these metabolite-associated genes with the 88 core network pharmacology targets yielded four candidate overlapping targets: APRT, NT5M, ADK, and HPRT1. Further analysis of the metabolite-reaction-enzyme-gene network linked all four candidate targets to deoxyguanosine-related metabolic reactions. The four candidate targets were then mapped back to the predicted target profiles of the 15 blood-absorbed prototype constituents of SHD. This analysis identified morroniside, loganin, and ginsenoside Rb1 as blood-absorbed prototype constituents predicted to be associated with one or more of these candidate targets. Molecular docking further suggested favorable potential interactions between these constituents and their corresponding candidate targets.

CONCLUSION: SHD ameliorated SD-induced cognitive impairment and hippocampal histopathological damage in mice. These effects were associated with reduced hippocampal neuroinflammation and partial normalization of NRG1/ErbB4-related PV and synaptic plasticity markers. Integrated network pharmacology and metabolomics analyses further suggest that purine metabolism may represent a potential link between SD-induced systemic metabolic disturbances and the effects of SHD. These findings provide experimental evidence for the pharmacological basis of the traditional use of SHD for conditions associated with forgetfulness, insomnia, and mental disturbance.