Investigation of the underling mechanism of ketamine for antidepressant effects in treatment-refractory affective disorders via molecular profile analysis

摘要

Ketamine elicits a rapid antidepressant effect in treatment-refractory affective disorders. The aim of the present study was to elucidate the underlying mechanism of this effect and to identify potential targets of ketamine for antidepressant effects. and datasets were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified in hippocampus or striatum samples treated with ketamine, phencyclidyne or memantine compared with a saline or normal group at 1, 2, 4 and 8 h. The overlapping DEGs were the DEGs in both hippocampus and striatum samples. Kyoto Encyclopedia of Genes and Genomes and BioCyc databases were used to perform functional annotation and pathway analyses. Protein-protein interactions (PPIs) were predicted using Search Tool for the Retrieval of Interacting Genes/Proteins version 9.1 for the DEGs in the striatum samples treated with ketamine, phencyclidine or memantine compared with normal samples. Reverse transcription-quantitative polymerase chain reaction was performed to determine mRNA levels. Perilipin 4 (Plin4), serum/glucocorticoid regulated kinase 1 (Sgk1), kruppel like factor 2 (Klf2) and DDB1 and CUL4 associated factor 12 like 1 (Dcaf12l1) were the overlapping DEGs in the striatum samples treated with the three drugs at different time points. The mRNA expression levels of Plin4, Sgk1 and Klf2 were significantly higher (P<0.05), and the mRNA expression level of Dcaf12l1 was significantly lower in the striatum samples of the ketamine-treated group compared with the control group in an in vivo experiment. Both Sgk1 and Klf2 were enriched in the ‘forkhead box O (FoxO) signaling pathway’, and Sgk1 was additionally enriched in the ‘mechanistic target of rapamycin kinase (mTOR) signaling pathway’. PPI networks of DEGs in the striatum samples treated with ketamine, phencyclidine and memantine compared with normal samples were constructed, and Klf2 was involved in more pairs and was therefore a gene hub in the three networks. The four genes, Plin4, Sgk1, Klf2 and Dcaf12l1, were differentially expressed in all of the groups that treated with the three drugs and their expression levels were verified in in vivo experiments. The FoxO and mTOR signaling pathways may be involved in the underlying mechanism of the antidepressant effects of ketamine, and Plin4, Sgk1, Klf2 and Dcaf12l1 may be potential biomarkers for depression in N-methyl-D-aspartic acid receptor antagonist treatment.