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

Abstract

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. GSE73798 and GSE73799 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.

The Emerging Role of SGK1 (Serum- and Glucocorticoid-Regulated Kinase 1) in Major Depressive Disorder: Hypothesis and Mechanisms

“…Park et al, 2019;Kryst et al, 2020). Under these specific conditions, the trend of SGK1 appears paradoxical with respect to that observed in the classic stress-dependent forms of depression (Ficek et al, 2016;Qiao et al, 2019). The explanations for this paradoxical up-regulation of SGK1 in response to the ketamine treatment could lie in at least two key points: first, the neuronal model of glutamatergic activation differs from the canonical assessments of dopaminergic and serotoninergic neurons target for classical anti-depressants; second, it should be borne in mind that the rapid effect of ketamine is accompanied by a controlled dissociative state that could be related to high levels of anxiety-dependent stress probably with increase glucocorticoid release.…”

“…The explanations for this paradoxical up-regulation of SGK1 in response to the ketamine treatment could lie in at least two key points: first, the neuronal model of glutamatergic activation differs from the canonical assessments of dopaminergic and serotoninergic neurons target for classical anti-depressants; second, it should be borne in mind that the rapid effect of ketamine is accompanied by a controlled dissociative state that could be related to high levels of anxiety-dependent stress probably with increase glucocorticoid release. It is interesting to note that in response to the treatment with ketamine and to the ketamine-dependent SGK1 activation, a deep modulation in the FOXO activity (Qiao et al, 2019) and presumably in its transcriptional functionality has been also noticed, which could, in turn, explain the rapidity of the antidepressant effects of ketamine. However, further studies will be necessary to understand the potential role of SGK1 as a pharmacological target for the ketamine and its derivatives in depressive conditions refractory to traditional therapies.…”

Identification of the significant pathways of Banxia Houpu decoction in the treatment of depression based on network pharmacology

“…In the pathway, Hypoxia-inducible factor (HIF-1) was a main regulator in hypoxia response and played a role in energy supply in depression through neurotransmitter transmission [ 50 ]. (6) Other pathways in our result ( Fig 4B ) were indirectly linked to depression, in terms of nerve growth and inflammation, such as FoxO signaling pathway [ 70 , 71 ], Jak-STAT signaling pathway [ 72 , 73 ], prolactin signaling pathway [ 74 , 75 ] and TGF-beta signaling pathway [ 76 , 77 ].…”

“…4B) were indirectly linked to depression, in terms of nerve growth and inflammation, such as FoxO signaling pathway [70,71], Jak-STAT signaling pathway [72,73], prolactin signaling pathway [74,75] and TGF-beta signaling pathway [76,77].…”

Effects of inhibiting mTOR with rapamycin on behavior, development, neuromuscular physiology, and cardiac function in larval Drosophila

“…Activation of the mTORC1 signaling pathway has been shown increase glutamate receptors in hippocampal cells and play an important role in memory and learning in mice (Hsu et al, 2019). With the relatively newfound interest of studying mTOR in neuronal physiology, the potential therapeutic use of rapamycin and other mTOR inhibitors in neuropsychiatric and other diseases has also increased (Hasty, 2010; Heard et al, 2018; Hosoi et al, 1998; Stern and Berliner, 2019; Qiao et al, 2019).…”