Mechanism of essential oil from Schizonepeta tenuifolia in treatment of depression based on network pharmacology and experimental verification / 中国中药杂志

This paper aimed to explore the antidepressant effect of the essential oil from Schizonepeta tenuifolia Briq.(EOST) on the treatment of depression and its mechanism by using a combination of network pharmacology and the mouse model of lipopolysaccharide(LPS)-induced depression. The chemical components in EOST were identified using gas chromatography-mass spectrometer(GC-MS), and 12 active components were selected as the study objects. The targets related to EOST were obtained by Traditional Chinese Medicines Systems Pharmacology(TCMSP) and SwissTargetPrediction database. The targets related to depression were screened out through GeneCards, Therapeutic Target Database(TTD), and Online Mendelian Inheritance in Man(OMIM) database. The Venny 2.1 was applied to screen out the common targets of EOST and depression. The targets were imported into Cytoscape 3.7.2 to generate "drug-active component-diease-target" network diagram. The protein-protein interaction(PPI) network was constructed using STRING 11.5 database and Cytoscape 3.7.2, and the core targets were screened out. DAVID 6.8 database was used for Gene Ontology(GO) func-tional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis, and subsequently the enrichment results were visualized through the bioinformatics platform. The mouse model of depression was induced by intraperitoneally injecting with LPS in mice. Before modeling, mice were administrated orally with EOST. The antidepressant effect of EOST was evalua-ted by tail suspension test(TST), forced swimming test(FST), and novelty suppressed feeding test(NSFT) after modeling. The content of interleukin(IL)-1β was determined by enzyme-linked immunosorbent assay(ELISA), and the protein expression levels of IL-1β and pro IL-1β in the hippocampus were determined by Western blot. There were 12 main components and 179 targets in EOAT, of which, 116 targets were related to depression, mainly involved in neuroactive ligand-receptor interaction, calcium signaling pathway, and cyclic adenosine monophosphate(cAMP) signaling pathway. Biological processes such as synaptic signal transduction, G-protein coupled receptor signaling pathway, and chemical synaptic transmission were involved. Molecular functions such as neurotransmitter receptor activity, RNA polymerase Ⅱ transcription factor activity, and heme binding were involved. In mice experiments, the results showed that EOST at 100 mg·kg~(-1) and 50 mg·kg~(-1) significantly shortened the immobility time in TST and FST as well as the feeding latency in NSFT compared with the model group, decreased the levels of serum IL-1β and NO, and reduced the protein expression levels of IL-1β and pro IL-1β in the hippocampus. In conclusion, EOST shows a good antidepressant effect in a multi-component, multi-target, and multi-pathway manner. The mechanism may be attributed to the fact that EOST can down-regulate the protein expression levels of IL-1β and pro IL-1β, decrease the release of inflammatory factors, and reduce neuroinflammation response.

Antidepressant Effect of n-Butyl Alcohol Extracts from Xiaoyaosan via IGF-1Rβ/PI3K/Akt Pathway / 中国实验方剂学杂志

Objective:To investigate the intervention effect of <italic>n</italic>-butyl alcohol extracts from Xiaoyaosan against depression-like behavior induced by chronic unpredictable mild stress （CUMS） in model mice and the role of insulin-like growth factor-1 receptor <italic>β</italic> （IGF-1R<italic>β</italic>）/phosphatidylinositol-3 kinase （PI3K）/protein kinase B （Akt） signaling pathway in such intervention. Method:The effective dose of n-butyl alcohol extracts from Xiaoyaosan was preliminarily determined in model mice with behavioral despair. Then the male C57BL/6 mice were randomly divided into the blank group， model group， fluoxetine group， Xiaoyaosan group， and the low- （20 g·kg^-1） and high-dose （40 g·kg^-1） <italic>n</italic>-butyl alcohol extract groups. The mice in all groups except for the blank group were exposed to CUMS for inducing the depression-like behavior， which was judged by the sucrose preference test （SPT）. The successfully modeled mice in the medication groups were intragastrically administered with the corresponding drugs， whereas those in the blank and model groups were treated with an equal volume of solvent for five successive weeks. Following the SPT， tail suspension test （TST）， and novelty suppressed feeding test （NSFT） at the end of the fifth week， the insulin-like growth factor-1 （IGF-1） levels in mouse serum and hippocampus were measured by enzyme-linked immunosorbent assay （ELISA）. The average optical density （<italic>IA</italic>） of Nissl bodies in mouse hippocampal CA3 region was detected by toluidine blue staining. The 5-bromo-2-deoxyuridine （Brdu） and doublecortin （DCX） expression in the dentate gyrus （DG） was assayed using immunofluorescence method. The protein expression levels of IGF-1R<italic>β</italic>， PI3K， phosphorylated-PI3K （p-PI3K）， Akt， p-Akt， cysteine aspartic acid-specific protease 3 （Caspase-3）， and cleaved Caspase-3 in the hippocampus were determined by Western blot. Result:The results of forced swimming test and TST showed that n-butyl alcohol extracts from Xiaoyaosan at 9.1 and 40 g·kg^-1 both significantly shortened the immobility time of mice （<italic>P</italic><0.05， <italic>P</italic><0.01）， indicating that the effective dose ranged from 9.1-40 g·kg^-1. Compared with the model control， the n-butyl alcohol extracts from Xiaoyaosan at 20 and 40 g·kg^-1 significantly increased the sucrose preference percentage （<italic>P</italic><0.05， <italic>P</italic><0.01）， shortened the immobility time in TST （<italic>P</italic><0.01） and the feeding latency in NSFT （<italic>P</italic><0.01）， reversed the down-regulated IGF-1 content in mouse serum and hippocampus （<italic>P</italic><0.01）， increased the AOD of Nissl bodies in the hippocampal CA3 region （<italic>P</italic><0.01）， promoted the expression of Brdu and DCX in DG （<italic>P</italic><0.05， <italic>P</italic><0.01）， and down-regulated the protein expression levels of IGF-1R<italic>β</italic> （<italic>P</italic><0.05， <italic>P</italic><0.01）， p-PI3K/PI3K （<italic>P</italic><0.05， <italic>P</italic><0.01）， p-Akt/Akt （<italic>P</italic><0.05）， and cleaved Caspase-3/Caspase-3 in the hippocampus of CUMS mice. Conclusion:The n-butyl alcohol extracts from Xiaoyaosan are equivalent to Xiaoyaosan in inhibiting expression. They alleviate the depression-like behavior in CUMS mice， induce the production of Nissl bodies in hippocampal CA3 region， enhance neuronal proliferation and differentiation in DG， and facilitate neurogenesis. All these may be related to the inhibition of over-activated IGF-1R<italic>β</italic>/PI3K/Akt pathway and the reduction of neuronal apoptosis.