Clozapine promotes glycolysis and myelin lipid synthesis in cultured oligodendrocytes

Steiner, Johann, Martins-de-Souza, Daniel, Schiltz, Kolja, Sarnyai, Zoltan, Westphal, Sabine, Isermann, Berend, Dobrowolny, Henrik, Turck, Christoph W., Bogerts, Bernhard, Bernstein, Hans-Gert, Horvath, Tamas L., Schild, Lorenz, and Keilhoff, Gerburg (2014) Clozapine promotes glycolysis and myelin lipid synthesis in cultured oligodendrocytes. Frontiers in Cellular Neuroscience, 8. pp. 1-11.

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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.

Item ID: 37352
Item Type: Article (Refereed Research - C1)
Keywords: schizophrenia, oligodendrocytes, clozapine, haloperidol, glycolysis, myelin
Additional Information:

© 2014 Steiner, Martins-de-Souza, Schiltz, Sarnyai, Westphal, Isermann, Dobrowolny, Turck, Bogerts, Bernstein, Horvath, Schild and Keilhoff. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

ISSN: 1662-5102
Funders: São Paulo Research Foundation (FAPESP)
Projects and Grants: FAPESP grant no. 13/08711-3
Date Deposited: 02 Apr 2015 04:28
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1109 Neurosciences > 110903 Central Nervous System @ 50%
11 MEDICAL AND HEALTH SCIENCES > 1103 Clinical Sciences > 110319 Psychiatry (incl Psychotherapy) @ 50%
SEO Codes: 92 HEALTH > 9204 Public Health (excl. Specific Population Health) > 920410 Mental Health @ 50%
97 EXPANDING KNOWLEDGE > 970111 Expanding Knowledge in the Medical and Health Sciences @ 50%
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