title: Clozapine promotes glycolysis and myelin lipid synthesis in cultured oligodendrocytes.
abstract: Clozapine displays stronger systemic metabolic side effects than haloperidol and it has been hypothesized that therapeutic antipsychotic and adverse metabolic effects of these drugs are related. Considering that cerebral disconnectivity through oligodendrocyte dysfunction has been implicated in schizophrenia, it is important to determine the effect of these drugs on oligodendrocyte energy metabolism and myelin lipid production. Effects of clozapine and haloperidol on glucose and myelin lipid metabolism were evaluated and compared in cultured OLN-93 oligodendrocytes. First, glycolytic activity was assessed by measurement of extra- and intracellular glucose and lactate levels. Next, the expression of glucose (GLUT) and monocarboxylate (MCT) transporters was determined after 6 and 24 h. And finally mitochondrial respiration, acetyl-CoA carboxylase, free fatty acids, and expression of the myelin lipid galactocerebroside were analyzed. Both drugs altered oligodendrocyte glucose metabolism, but in opposite directions. Clozapine improved the glucose uptake, production and release of lactate, without altering GLUT and MCT. In contrast, haloperidol led to higher extracellular levels of glucose and lower levels of lactate, suggesting reduced glycolysis. Antipsychotics did not alter significantly the number of functionally intact mitochondria, but clozapine enhanced the efficacy of oxidative phosphorylation and expression of galactocerebroside. Our findings support the superior impact of clozapine on white matter integrity in schizophrenia as previously observed, suggesting that this drug improves the energy supply and myelin lipid synthesis in oligodendrocytes. Characterizing the underlying signal transduction pathways may pave the way for novel oligodendrocyte-directed schizophrenia therapies.
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Magdeburg Magdeburg, Germany ; Center for Behavioral Brain Sciences Magdeburg, Germany ; Pembroke College, University of Cambridge Cambridge, UK.
authors.forename: Johann
authors.initials: J
authors.lastname: Steiner
authors.affiliation: Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP) Campinas, Brazil.
authors.forename: Daniel
authors.initials: D
authors.lastname: Martins-de-Souza
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Magdeburg Magdeburg, Germany ; Center for Behavioral Brain Sciences Magdeburg, Germany.
authors.forename: Kolja
authors.initials: K
authors.lastname: Schiltz
authors.affiliation: Laboratory of Psychiatric Neuroscience, James Cook University Townsville, QLD, Australia ; Comparative Genome Centre, James Cook University Townsville, QLD, Australia ; Centre for Biodiscovery and Molecular Development of Therapeutics, James Cook University Townsville, QLD, Australia ; Australian Institute of Tropical Health and Medicine, James Cook University Townsville, QLD, Australia.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Sarnyai
authors.affiliation: Institute of Clinical Chemistry and Pathobiochemistry, University of Magdeburg Magdeburg, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Westphal
authors.affiliation: Institute of Clinical Chemistry and Pathobiochemistry, University of Magdeburg Magdeburg, Germany.
authors.forename: Berend
authors.initials: B
authors.lastname: Isermann
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Magdeburg Magdeburg, Germany.
authors.forename: Henrik
authors.initials: H
authors.lastname: Dobrowolny
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry Munich, Germany.
authors.forename: Christoph W
authors.initials: CW
authors.lastname: Turck
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Magdeburg Magdeburg, Germany ; Center for Behavioral Brain Sciences Magdeburg, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Bogerts
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Magdeburg Magdeburg, Germany.
authors.forename: Hans-Gert
authors.initials: HG
authors.lastname: Bernstein
authors.affiliation: Section of Comparative Medicine, Yale University School of Medicine New Haven, CT, USA.
authors.forename: Tamas L
authors.initials: TL
authors.lastname: Horvath
authors.affiliation: Institute of Clinical Chemistry and Pathobiochemistry, University of Magdeburg Magdeburg, Germany.
authors.forename: Lorenz
authors.initials: L
authors.lastname: Schild
authors.affiliation: Institute of Biochemistry and Cell Biology, University of Magdeburg Magdeburg, Germany.
authors.forename: Gerburg
authors.initials: G
authors.lastname: Keilhoff
keywords: clozapine; glycolysis; haloperidol; myelin; oligodendrocytes; schizophrenia