title: Proteomic and metabolomic profiling reveals time-dependent changes in hippocampal metabolism upon paroxetine treatment and biomarker candidates.
abstract: Most of the commonly used antidepressants block monoamine reuptake transporters to enhance serotonergic or noradrenergic neurotransmission. Effects besides or downstream of monoamine reuptake inhibition are poorly understood and yet presumably important for the drugs' mode of action. In the present study we aimed at identifying hippocampal cellular pathway alterations in DBA/2 mice using paroxetine as a representative Selective Serotonin Reuptake Inhibitor (SSRI). Furthermore we identified biomarker candidates for the assessment of antidepressant treatment effects in plasma. Hippocampal protein levels were compared between chronic paroxetine- and vehicle-treated animals using in vivo(15)N metabolic labeling combined with mass spectrometry. We also studied the time course of metabolite level changes in hippocampus and plasma using a targeted polar metabolomics profiling platform. In silico pathway analyses revealed profound alterations related to hippocampal energy metabolism. Glycolytic metabolite levels acutely increased while Krebs cycle metabolite levels decreased upon chronic treatment. Changes in energy metabolism were influenced by altered glycogen metabolism rather than by altered glycolytic or Krebs cycle enzyme levels. Increased energy levels were reflected by an increased ATP/ADP ratio and by increased ratios of high-to-low energy purines and pyrimidines. In the course of our analyses we also identified myo-inositol as a biomarker candidate for the assessment of antidepressant treatment effects in the periphery. This study defines the cellular response to paroxetine treatment at the proteome and metabolome levels in the hippocampus of DBA/2 mice and suggests novel SSRI modes of action that warrant consideration in antidepressant development efforts.
authors.affiliation: Max Planck Institute of Psychiatry, Kraepelinstrasse 2-10, 80804 Munich, Germany; Graduate School of Systemic Neurosciences, Ludwig-Maximilians-University Munich, Planegg-Martinsried, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Webhofer
authors.forename: Philipp
authors.initials: P
authors.lastname: Gormanns
authors.forename: Stefan
authors.initials: S
authors.lastname: Reckow
authors.forename: Maria
authors.initials: M
authors.lastname: Lebar
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Maccarrone
authors.forename: Tonia
authors.initials: T
authors.lastname: Ludwig
authors.forename: Benno
authors.initials: B
authors.lastname: Pütz
authors.forename: John M
authors.initials: JM
authors.lastname: Asara
authors.forename: Florian
authors.initials: F
authors.lastname: Holsboer
authors.forename: Inge
authors.initials: I
authors.lastname: Sillaber
authors.forename: Walter
authors.initials: W
authors.lastname: Zieglgänsberger
authors.forename: Christoph W
authors.initials: CW
authors.lastname: Turck
mesh_terms: D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology*; D015415:Biomarkers / Q000097:blood; D002853:Chromatography, Liquid; D016002:Discriminant Analysis; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D051379:Mice; D008811:Mice, Inbred DBA; D017374:Paroxetine / Q000494:pharmacology*; D020543:Proteome / Q000378:metabolism*; D040901:Proteomics; D053719:Tandem Mass Spectrometry; D013997:Time Factors
chemical_list: D018687:Antidepressive Agents, Second-Generation; D015415:Biomarkers; D020543:Proteome; D017374:Paroxetine