Integrated metabolomic and transcriptomic analysis reveals the neurotoxicity and mechanisms of Shengfu Pian
Background: The mechanisms underlying neurological toxicity are complex. Shengfu Pian (SFP), a traditional Chinese medicine, has drawn increasing attention due to its potential neurotoxic effects.Methods: To investigate the neurotoxic mechanisms of SFP, we first applied non-targeted serum chemomics to characterize its chemical constituents in vitro, as well as in blood and brain samples. We then integrated brain transcriptomics with serum and brain metabolomics to identify dysregulated neural pathways. Key targets were further validated using ELISA and Western blot analyses. The levels of 11 neurotransmitters in brain tissue and serum were determined using targeted metabolomics.Results: The bioavailable components of SFP decoction (0.36 g/kg) were mainly alkaloids, with 29 compounds detected in the blood and 9in brain tissue. Repeated administration induced inflammatory responses in mouse neurons and promoted the activation of astrocytes and microglia. Transcriptomic analysis revealed 253 differentially expressed genes (DEGs, 161 up/92 down), among which Cyp1a2 was identified as a central gene associated with neurotoxicity. Serum metabolomics uncovered 27 disturbed metabolites (5 up/22 down), primarily involved in tryptophan metabolism. Brain metabolomics showed 46 altered metabolites (30 up/16 down), enriched in purine metabolism. Integrated omics analysis and experimental validation indicated that repeated oral SFP administration disrupted tryptophan metabolism, and reduced circulating indole derivatives. This led to dysregulation of the brain AhR-CYP1A2 axis, which increased the level of acetylcholine, disturbed purine nucleotide compensation, and ultimately elicited neurotoxic manifestations including seizures in mice.Conclusion: Although preliminary and based on a limited sample size without clinical validation, this study highlights the critical role of intestinal metabolism in mediating neurotoxicity. It provides novel mechanistic insights and a foundation for further clinical safety evaluation of SFP and other compounds with potential neurotoxic effects.