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Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 392, Issue 10, pp 1209–1223 | Cite as

In vitro effects of antipsychotics on mitochondrial respiration

  • Tereza Cikánková
  • Zdeněk Fišar
  • Yousra Bakhouche
  • Matej Ľupták
  • Jana HroudováEmail author
Original Article

Abstract

Assessment of drug-induced mitochondrial dysfunctions is important in drug development as well as in the understanding of molecular mechanism of therapeutic or adverse effects of drugs. The aim of this study was to investigate the effects of three typical antipsychotics (APs) and seven atypical APs on mitochondrial bioenergetics. The effects of selected APs on citrate synthase, electron transport chain complexes (ETC), and mitochondrial complex I- or complex II-linked respiratory rate were measured using mitochondria isolated from pig brain. Complex I activity was decreased by chlorpromazine, haloperidol, zotepine, aripiprazole, quetiapine, risperidone, and clozapine. Complex II + III was significantly inhibited by zotepine, aripiprazole, quetiapine, and risperidone. Complex IV was inhibited by zotepine, chlorpromazine, and levomepromazine. Mitochondrial respiratory rate was significantly inhibited by all tested APs, except for olanzapine. Typical APs did not exhibit greater efficacy in altering mitochondrial function compared to atypical APs except for complex I inhibition by chlorpromazine and haloperidol. A comparison of the effects of APs on individual respiratory complexes and on the overall mitochondrial respiration has shown that mitochondrial functions may not fully reflect the disruption of complexes of ETC, which indicates AP-induced modulation of other mitochondrial proteins. Due to the complicated processes associated with mitochondrial activity, it is necessary to measure not only the effect of the drug on individual mitochondrial enzymes but also the respiration rate of the mitochondria or a similar complex process. The experimental approach used in the study can be applied to mitochondrial toxicity testing of newly developed drugs.

Keywords

Antipsychotics Citrate synthase Electron transport chain complexes Mitochondrial respiration 

Abbreviations

AP

Antipsychotic

COX

Complex IV, cytochrome c oxidase

CS

Citrate synthase

ETC

Electron transport chain

MARTA

Multi-acting receptor targeted antipsychotics

OXPHOS

Oxidative phosphorylation

ROS

Reactive oxygen species

Notes

Acknowledgments

This work was supported by the Czech Science Foundation (grant number 17-07585Y) and by Charles University Grant Agency (grant number 34119), Czech Republic. The authors thank Zdeněk Hanuš for his assistance.

Author’s contribution

JH and ZF conceived and designed research. TC, YB, ML, and JH conducted experiments. TC, JH, and ZF analyzed data and wrote the manuscript. All authors read and approved the manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that there is no conflict of interest regarding the publication of this paper.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Tereza Cikánková
    • 1
  • Zdeněk Fišar
    • 1
  • Yousra Bakhouche
    • 1
  • Matej Ľupták
    • 2
  • Jana Hroudová
    • 1
    • 2
    Email author
  1. 1.Department of Psychiatry, First Faculty of MedicineCharles University and General University Hospital in PraguePrague 2Czech Republic
  2. 2.Institute of Pharmacology, First Faculty of MedicineCharles University and General University Hospital in PraguePrague 2Czech Republic

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