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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Clozapine promotes glycolysis and myelin lipid synthesis in cultured oligodendrocytes

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Author(s):
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Steiner, Johann [1, 2, 3] ; Martins-de-Souza, Daniel [4] ; Schiltz, Kolja [1, 2] ; Sarnyai, Zoltan [5, 6, 7, 8] ; Westphal, Sabine [9] ; Isermann, Berend [9] ; Dobrowolny, Henrik [2] ; Turck, Christoph W. [10] ; Bogerts, Bernhard [1, 2] ; Bernstein, Hans-Gert [2] ; Horvath, Tamas L. [11] ; Schild, Lorenz [9] ; Keilhoff, Gerburg [12]
Total Authors: 13
Affiliation:
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[1] Ctr Behav Brain Sci, Magdeburg - Germany
[2] Univ Magdeburg, Dept Psychiat & Psychotheraphy, D-39120 Magdeburg - Germany
[3] Univ Cambridge, Pembroke Coll, Cambridge - England
[4] Univ Campinas UNICAMP, Inst Biol, Dept Biochem & Tissue Biol, Lab Neuroprote, Campinas - Brazil
[5] James Cook Univ, Lab Psychiat Neurosci, Townsville, Qld - Australia
[6] James Cook Univ, Comparat Genome Ctr, Townsville, Qld - Australia
[7] James Cook Univ, Ctr Biodiscovery & Mol Dev Therapeut, Townsville, Qld - Australia
[8] James Cook Univ, Australian Inst Trop Hlth & Med, Townsville, Qld - Australia
[9] Univ Magdeburg, Inst Clin Chem & Pathobiochem, D-39106 Magdeburg - Germany
[10] Max Planck Inst Psychiat, Dept Translat Res Psychiat, D-80804 Munich - Germany
[11] Yale Univ, Sch Med, Comparat Med Sect, New Haven, CT 06510 - USA
[12] Univ Magdeburg, Inst Biochem & Cell Biol, D-39106 Magdeburg - Germany
Total Affiliations: 12
Document type: Journal article
Source: FRONTIERS IN CELLULAR NEUROSCIENCE; v. 8, NOV 18 2014.
Web of Science Citations: 18
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. (AU)

FAPESP's process: 13/08711-3 - Developing a predictive test for a successful medication response and understanding the molecular bases of schizophrenia through proteomics
Grantee:Daniel Martins-de-Souza
Support Opportunities: Research Grants - Young Investigators Grants