title: A targeted multiplexed proteomic investigation identifies ketamine-induced changes in immune markers in rat serum and expression changes in protein kinases/phosphatases in rat brain.
abstract: There is substantial interest in the N-methyl-d-aspartate (NMDA) receptor antagonist ketamine in psychiatric research because it exerts acute psychotomimetic and rapid antidepressant effects in rodents and humans. Here, we investigated proteomic changes in brain and serum after acute treatment of rats with ketamine using two targeted proteomic profiling methods. Multiplex immunoassay profiling of serum identified altered levels of interleukin 4, tumor necrosis factor alpha, and fibroblast growth factor 9, suggesting a link between ketamine exposure and peripheral inflammation and growth factor dysregulation. Selected reaction monitoring mass spectrometry profiling of rat brain tissue found that proteomic changes occurred in the frontal cortex and to a greater extent in the hippocampus. This involved changes in signaling kinases and proteases such as protein kinase C beta, neurochondrin (NCDN), calcineurin, extracellular signal-regulated kinsase 1 (ERK1), and mammalian target of rapamycin (MTOR). Furthermore, altered levels were found for proteins associated with neurotransmitter metabolism (mitochondrial aspartate aminotransferase, catechol O-methyl transferase, synaptic vesicle endo-/exocytosis (vesicle fusing ATPase (NSF), synapsin 1 (SYN1), syndapin-1 (PACN1)). Consistent with previous global proteomic studies, we confirmed known changes in mitochondrial complex I, prohibitin (PHB) and neurofilament proteins (neurofilament light chain and α-internexin (AINX)). Taken together, the proteomic changes parallel those described in human psychiatric pathology. The results will help to elucidate ketamine's mechanism of action, which will facilitate development of novel drugs for the treatment of schizophrenia and major depressive disorder.
authors.affiliation: Department of Chemical Engineering and Biotechnology, University of Cambridge , Cambridge CB2 1QT, United Kingdom.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Wesseling
authors.forename: Hassan
authors.initials: H
authors.lastname: Rahmoune
authors.forename: Mark
authors.initials: M
authors.lastname: Tricklebank
authors.forename: Paul C
authors.initials: PC
authors.lastname: Guest
authors.forename: Sabine
authors.initials: S
authors.lastname: Bahn
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D007118:Immunoassay; D007649:Ketamine / Q000494:pharmacology*; D013058:Mass Spectrometry; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D025341:Principal Component Analysis; D000091402:Prohibitins; D011494:Protein Kinases / Q000378:metabolism*; D040901:Proteomics / Q000379:methods*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors
chemical_list: D015415:Biomarkers; C000717328:PHB protein, human; C000717332:Phb protein, rat; D000091402:Prohibitins; D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine; D011494:Protein Kinases; D010744:Phosphoric Monoester Hydrolases
keywords: MSstats; NMDA-receptor antagonist; SRM; animal model; ketamine; major depressive disorder; multiplex immunoassay; pharmacological treatment; rat; schizophrenia