Exploring the Molecular Targets for the Antidepressant and Antisuicidal Effects of Ketamine Enantiomers by Using Network Pharmacology and Molecular Docking

Abstract

Ketamine, a racemic mixture of esketamine (S-ketamine) and arketamine (R-ketamine), has received particular attention for its rapid antidepressant and antisuicidal effects. NMDA receptor inhibition has been indicated as one of the main mechanisms of action of the racemic mixture, but other pharmacological targets have also been proposed. This study aimed to explore the possible multiple targets of ketamine enantiomers related to their antidepressant and antisuicidal effects. To this end, targets were predicted using Swiss Target Prediction software for each ketamine enantiomer. Targets related to depression and suicide were collected by the Gene Cards database. The intersections of targets were analyzed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Network pharmacology analysis was performed using Gene Mania and Cytoscape software. Molecular docking was used to predict the main targets of the network. The results indicated that esketamine and arketamine share some biological targets, particularly NMDA receptor and phosphodiesterases 3A, 7A, and 5A but have specific molecular targets. While esketamine is predicted to interact with the GABAergic system, arketamine may interact with macrophage migration inhibitory factor (MIF). Both ketamine enantiomers activate neuroplasticity-related signaling pathways and show addiction potential. Our results identified novel, poorly explored molecular targets that may be related to the beneficial effects of esketamine and arketamine against depression and suicide.

(R)-(-)-Ketamine: The Promise of a Novel Treatment for Psychiatric and Neurological Disorders

“…Additional new data on the mechanisms by which ( R )-ketamine transduces its antidepressant-like effects have also been disclosed. These data provide new information on the impact of ( R )-ketamine on biological pathways not previously discussed, such as macrophage migration inhibitory factor [ 92 ], pathways associated with the microRNA mi(R)-132-5p [ 93 , 94 ], novel ERK-NRBP1-CREB-BDNF pathways in microglia [ 95 ], the gut–brain axis [ 96 ], and neural myelination, where ( R )-ketamine has greater efficacy than ( S )-ketamine [ 97 ], as well as immune function and inflammatory processes [ 78 , 98 , 99 , 100 ]. It is important to recognize that multiple other potential mechanisms of action might be relevant but have not been interrogated yet to as great an extent.…”