Abstract:Objective: To investigate the anticonvulsant mechanisms of bile acid monomer compounds cholic acid (CA) and deoxycholic acid (DCA). Methods: Male SD rats were randomly divided into blank group, model group, positive drug group (sodium valproate, 189 mg/kg), CA group (60 mg/kg), and DCA group (60 mg/kg), with 9 rats in each group. The blank group and model group were given placebo, and each treatment group was pre-treated 1 h before modeling, and continuously treated for 16 d. A seizure rat model was established using a water bath at (45±0.5) °C, with a bath given every other day for a total of 8 times. The seizure onset time, seizure termination time, and severity of seizure behavior of rats were observed and recorded. Meanwhile, the levels of TNF-α, IL-6, IL-1β in rat serum and hippocampal tissues, as well as the contents of glutamate(Glu) and γ-aminobutyric acid(GABA) in hippocampal tissues were detected. hematoxylin-eosin (HE) staining was used to observe the pathological damage of hippocampal neurons. Metabolomic analysis of rat serum was conducted using ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Results: Compared with the model group, all treatment groups significantly prolonged the latency of seizures, significantly reduced the duration of seizures (P<0.001); the positive drug group and DCA group significantly reduced the severity of seizures (P<0.001, P<0.01), while there was no significant difference in the CA group. Compared with the blank group, the contents of IL-1β TNF-α, IL-6 in serum and hippocampal tissues of the model group were significantly increased (P<0.001), and the contents of Glu and GABA in hippocampus were also significantly increased (P<0.001). Compared with the model group, the effects produced by the DCA group and positive drug group were similar, both of which could reduce the levels of various biochemical indicators (P<0.001), while compared with the model group, the CA group could significantly reduce all indicators except TNF-α in serum and IL-6 in the hippocampus (P<0.01). HE staining results of hippocampal tissues showed that compared with the blank group, the pyramidal cells in the hippocampus of rats in the model group were contracted, with smaller volume, darker staining, enhanced alkalinity, and the unclear cytoplasmic nuclear boundaries; compared with the model group, the morphology of hippocampal neurons in each treatment group was significantly improved. Among them, the morphology of hippocampal neurons in the DCA group was similar to that in the positive drug group. A total of 312 differential compounds were identified in serum metabolomics analysis. Through PCA and OPLS-DA analysis, 9 differential compounds were selected. The results of metabolic pathway enrichment showed that the anticonvulsant effects of CA and DCA mainly involve the citric acid cycle, amino acid metabolism, and butyric acid metabolism pathways. Conclusion: CA and DCA have certain improvement effects on behavioral and biochemical indicators of febrile seizure rats, and their mechanisms of action may be related to energy metabolism, amino acid metabolism, and short-chain fatty acid metabolism during seizures.