胆酸和去氧胆酸抗惊厥作用的血清代谢组学研究OA北大核心CSTPCD

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 a control group,a model group,a sodium valproate or valproic acid(VPA),(189 mg/kg),a CA group(60 mg/kg),and a DCA group(60 mg/kg),with nine rats in each group.The rats in the control group and model group were given placebo,and the mice in 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±0.5)℃,with a bath given every other day for a total of eight times.The seizure onset time,seizure termination time,and the severity of seizure behavior of rats were observed and recorded.Meanwhile,the levels of interleukin 1β(IL-1β),interleukin 6(IL-6),and tumor necrosis factor α(TNF-α)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 performed using the 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 but significantly reduced the duration of seizures(P＜0.001);both the VPA group and DC A 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 control group,the contents of IL-1 β TNF-α,and 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 DC A group and the VPA group were similar,both of which reduced the levels of various biochemical indicators(P＜0.001),while the CA group significantly reduced all indicators except the TNF-α level in serum and the IL-6 level in the hippocampus(P＜0.01).HE staining results of hippocampal tissues showed that compared with the control group,the pyramidal cells in the hippocampus of rats in the model group were contracted,with a smaller volume,a darker staining,an 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 DC A group was similar to that in the VPA group.A total of 312 differential compounds were identified in serum metabolomics analysis.Through principal component analysis(PCA)and orthogonal partial least squares-discriminant analysis(OPLS-DA)analysis,nine differential compounds were selected.The results of metabolic pathway enrichment showed that the anticonvulsant effects of CA and DCA were mainly involved 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 rats with febrile seizures,and their mechanisms of action may be correlated with energy metabolism,amino acid metabolism,and short-chain fatty acid metabolism during seizures.