Time-dependent metabolomic profiling of Ketamine drug action reveals hippocampal pathway alterations and biomarker candidates.
Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, has fast-acting antidepressant activities and is used for major depressive disorder (MDD) patients who show treatment resistance towards drugs of the selective serotonin reuptake inhibitor (SSRI) type. In order to better understand Ketamine's mode of action, a prerequisite for improved drug development efforts, a detailed understanding of the molecular events elicited by the drug is mandatory. In the present study we have carried out a time-dependent hippocampal metabolite profiling analysis of mice treated with Ketamine. After a single injection of Ketamine, our metabolomics data indicate time-dependent metabolite level alterations starting already after 2 h reflecting the fast antidepressant effect of the drug. In silico pathway analyses revealed that several hippocampal pathways including glycolysis/gluconeogenesis, pentose phosphate pathway and citrate cycle are affected, apparent by changes not only in metabolite levels but also connected metabolite level ratios. The results show that a single injection of Ketamine has an impact on the major energy metabolism pathways. Furthermore, seven of the identified metabolites qualify as biomarkers for the Ketamine drug response.
Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
K
K
Weckmann
Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
C
C
Labermaier
Division of Signal Transduction, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
J M
JM
Asara
Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
M B
MB
Müller
Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
C W
CW
Turck
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D015415:Biomarkers / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism*; D007649:Ketamine / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D053858:Metabolic Networks and Pathways / Q000187:drug effects*; D055432:Metabolomics; D051379:Mice; D008810:Mice, Inbred C57BL; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors
D015415:Biomarkers; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine