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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

Clozapine promotes glycolysis and myelin lipid synthesis in cultured oligodendrocytes

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Steiner, Johann [1, 2, 3] ; Martins-de-Souza, Daniel [4] ; Schiltz, Kolja [2, 1] ; 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]
Número total de Autores: 13
Afiliação do(s) autor(es):
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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
Número total de Afiliações: 12
Tipo de documento: Artigo Científico
Citações Web of Science: 16

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)

Processo FAPESP: 13/08711-3 - Desenvolvimento de um teste preditivo para medicação bem sucedida e compreensão das bases moleculares da esquizofrenia através da proteômica
Beneficiário:Daniel Martins-de-Souza
Linha de fomento: Auxílio à Pesquisa - Apoio a Jovens Pesquisadores