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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.
