Mitochondrial dysfunction is involved in the pathophysiology of psychiatric and neurodegenerative disorders and can be used as a modulator and/or predictor of treatment responsiveness. Understanding the mitochondrial effects of antidepressants is important to connect mitochondria with their therapeutic and/or adverse effects. Pig brain-isolated mitochondria were used to evaluate antidepressant-induced changes in the activity of electron transport chain (ETC) complexes, monoamine oxidase (MAO), mitochondrial respiratory rate, and ATP. Bupropion, escitalopram, fluvoxamine, sertraline, paroxetine, and trazodone were tested. All tested antidepressants showed significant inhibition of complex I and IV activities at high concentrations (50 and 100 µmol/L); complex II + III activity was reduced by all antidepressants except bupropion. Complex I-linked respiration was reduced by escitalopram >> trazodone >> sertraline. Complex II-linked respiration was reduced only by bupropion. Significant positive correlations were confirmed between complex I-linked respiration and the activities of individual ETC complexes. MAO activity was inhibited by all tested antidepressants, with SSRIs causing a greater effect than trazodone and bupropion. The results indicate a probable association between the adverse effects of high doses of antidepressants and drug-induced changes in the activity of ETC complexes and the respiratory rate of mitochondria. In contrast, MAO inhibition could be linked to the antidepressant, procognitive, and neuroprotective effects of the tested antidepressants.

• Keywords
• ATP, antidepressants, mitochondrial respiration, monoamine oxidase, oxidative phosphorylation, reactive oxygen species,
• Publication type
• Journal Article MeSH

The trends of novel AD therapeutics are focused on multitarget-directed ligands (MTDLs), which combine cholinesterase inhibition with additional biological properties such as antioxidant properties to positively affect neuronal energy metabolism as well as mitochondrial function. We examined the in vitro effects of 10 novel MTDLs on the activities of mitochondrial enzymes (electron transport chain complexes and citrate synthase), mitochondrial respiration, and monoamine oxidase isoform (MAO-A and MAO-B) activity. The drug-induced effects of 7-MEOTA-adamantylamine heterodimers (K1011, K1013, K1018, K1020, and K1022) and tacrine/7-MEOTA/6-chlorotacrine-trolox heterodimers (K1046, K1053, K1056, K1060, and K1065) were measured in pig brain mitochondria. Most of the substances inhibited complex I- and complex II-linked respiration at high concentrations; K1046, K1053, K1056, and K1060 resulted in the least inhibition of mitochondrial respiration. Citrate synthase activity was not significantly inhibited by the tested substances; the least inhibition of complex I was observed for compounds K1060 and K1053, while both complex II/III and complex IV activity were markedly inhibited by K1011 and K1018. MAO-A was fully inhibited by K1018 and K1065, and MAO-B was fully inhibited by K1053 and K1065; the other tested drugs were partial inhibitors of both MAO-A and MAO-B. The tacrine/7-MEOTA/6-chlorotacrine-trolox heterodimers K1046, K1053, and K1060 seem to be the most suitable molecules for subsequent in vivo studies. These compounds had balanced inhibitory effects on mitochondrial respiration, with low complex I and complex II/III inhibition and full or partial inhibition of MAO-B activity.

• Keywords
• Alzheimer’s disease, Cholinesterase inhibitors, Electron transport chain complexes, Mitochondrial respiration, Monoamine oxidase, Multitarget-directed ligands,
• MeSH
• Alzheimer Disease drug therapy   MeSH
• Cell Respiration drug effects   MeSH
• Energy Metabolism * drug effects   MeSH
• Monoamine Oxidase Inhibitors pharmacology   MeSH
• Mitochondria drug effects   enzymology   metabolism   MeSH
• Monoamine Oxidase metabolism   MeSH
• Swine MeSH
• Electron Transport Complex II metabolism   MeSH
• Tacrine chemistry   pharmacology   MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Monoamine Oxidase Inhibitors MeSH
• Monoamine Oxidase MeSH
• Electron Transport Complex II MeSH
• Tacrine MeSH

The evaluation of drug-induced mitochondrial impairment may be important in drug development as well as in the comprehension of molecular mechanisms of the therapeutic and adverse effects of drugs. The primary aim of this study was to investigate the effects of four drugs for treatment of depression (bupropion, fluoxetine, amitriptyline, and imipramine) and five drugs for bipolar disorder treatment (lithium, valproate, valpromide, lamotrigine, and carbamazepine) on cell energy metabolism. The in vitro effects of the selected psychopharmaca were measured in isolated pig brain mitochondria; the activities of citrate synthase (CS) and electron transport chain (ETC) complexes (I, II + III, and IV) and mitochondrial respiration rates linked to complex I and complex II were measured. Complex I was significantly inhibited by lithium, carbamazepine, fluoxetine, amitriptyline, and imipramine. The activity of complex IV was decreased after exposure to carbamazepine. The activities of complex II + III and CS were not affected by any tested drug. Complex I-linked respiration was significantly inhibited by bupropion, fluoxetine, amitriptyline, imipramine, valpromide, carbamazepine, and lamotrigine. Significant inhibition of complex II-linked respiration was observed after mitochondria were exposed to amitriptyline, fluoxetine, and carbamazepine. Our outcomes confirm the need to investigate the effects of drugs on both the total respiration rate and the activities of individual enzymes of the ETC to reveal the risk of adverse effects as well as to understand the molecular mechanisms leading to drug-induced changes in the respiratory rate. Our approach can be further replicated to study the mechanisms of action of newly developed drugs.

• Keywords
• Antidepressant, Citrate synthase, Electron transport chain complexes, Mitochondrial respiration, Mood-stabilizing drugs,
• MeSH
• Antidepressive Agents toxicity   MeSH
• Antimanic Agents toxicity   MeSH
• Cell Respiration drug effects   MeSH
• Electron Transport Chain Complex Proteins metabolism   MeSH
• Mitochondria drug effects   metabolism   MeSH
• Brain drug effects   metabolism   MeSH
• Oxidative Phosphorylation drug effects   MeSH
• Subcellular Fractions MeSH
• Sus scrofa MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Antidepressive Agents MeSH
• Antimanic Agents MeSH
• Electron Transport Chain Complex Proteins MeSH

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,
• MeSH
• Antipsychotic Agents toxicity   MeSH
• Energy Metabolism drug effects   MeSH
• Mitochondria drug effects   pathology   MeSH
• Brain drug effects   metabolism   MeSH
• Swine MeSH
• Electron Transport Complex I drug effects   metabolism   MeSH
• Electron Transport Complex II drug effects   metabolism   MeSH
• In Vitro Techniques MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Comparative Study MeSH
• Names of Substances
• Antipsychotic Agents MeSH
• Electron Transport Complex I MeSH
• Electron Transport Complex II MeSH

Impairment of mitochondrial metabolism, particularly the electron transport chain (ETC), as well as increased oxidative stress might play a significant role in pathogenesis of Alzheimer's disease (AD). Some effects of drugs used for symptomatic AD treatment may be related to their direct action on mitochondrial function. In vitro effects of pharmacologically different cognitives (galantamine, donepezil, rivastigmine, 7-MEOTA, memantine) and nootropic drugs (latrepirdine, piracetam) were investigated on selected mitochondrial parameters: activities of ETC complexes I, II + III, and IV, citrate synthase, monoamine oxidase (MAO), oxygen consumption rate, and hydrogen peroxide production of pig brain mitochondria. Complex I activity was decreased by galantamine, donepezil, and memantine; complex II + III activity was increased by galantamine. None of the tested drugs caused significant changes in the rate of mitochondrial oxygen consumption, even at high concentrations. Except galantamine, all tested drugs were selective MAO-A inhibitors. Latrepirdine, donepezil, and 7-MEOTA were found to be the most potent MAO-A inhibitors. Succinate-induced mitochondrial hydrogen peroxide production was not significantly affected by the drugs tested. The direct effect of cognitives and nootropics used in the treatment of AD on mitochondrial respiration is relatively small. The safest drugs in terms of disturbing mitochondrial function appear to be piracetam and rivastigmine. The MAO-A inhibition by cognitives and nootropics may also participate in mitochondrial neuroprotection. The results support the future research aimed at measuring the effects of currently used drugs or newly synthesized drugs on mitochondrial functioning in order to understand their mechanism of action.

• Keywords
• Cognitives, Mitochondrial respiration, Monoamine oxidase, Nootropics, Reactive oxygen species,
• MeSH
• Alzheimer Disease metabolism   MeSH
• Cholinesterase Inhibitors pharmacology   MeSH
• Donepezil MeSH
• Galantamine metabolism   MeSH
• Indans pharmacology   MeSH
• Cognition drug effects   MeSH
• Memantine pharmacology   MeSH
• Mitochondria drug effects   metabolism   MeSH
• Monoamine Oxidase drug effects   metabolism   MeSH
• Brain drug effects   metabolism   MeSH
• Nootropic Agents pharmacology   MeSH
• Piperidines pharmacology   MeSH
• Swine MeSH
• Rivastigmine pharmacology   MeSH
• Oxygen Consumption drug effects   MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Cholinesterase Inhibitors MeSH
• Donepezil MeSH
• Galantamine MeSH
• Indans MeSH
• Memantine MeSH
• Monoamine Oxidase MeSH
• Nootropic Agents MeSH
• Piperidines MeSH
• Rivastigmine MeSH

The aim of this study was to investigate changes in the activity of individual mitochondrial respiratory chain complexes (I, II/III, IV) and citrate synthase induced by pharmacologically different cannabinoids. In vitro effects of selected cannabinoids on mitochondrial enzymes were measured in crude mitochondrial fraction isolated from pig brain. Both cannabinoid receptor agonists, Δ(9)-tetrahydrocannabinol, anandamide, and R-(+)-WIN55,212-2, and antagonist/inverse agonists of cannabinoid receptors, AM251, and cannabidiol were examined in pig brain mitochondria. Different effects of these cannabinoids on mitochondrial respiratory chain complexes and citrate synthase were found. Citrate synthase activity was decreased only by Δ(9)-tetrahydrocannabinol and AM251. Significant increase in the complex I activity was induced by anandamide. At micromolar concentration, all the tested cannabinoids inhibited the activity of electron transport chain complexes II/III and IV. Stimulatory effect of anandamide on activity of complex I may participate on distinct physiological effects of endocannabinoids compared to phytocannabinoids or synthetic cannabinoids. Common inhibitory effect of cannabinoids on activity of complex II/III and IV confirmed a non-receptor-mediated mechanism of cannabinoid action on individual components of system of oxidative phosphorylation.

• MeSH
• Cannabinoid Receptor Antagonists pharmacology   MeSH
• Citrate (si)-Synthase metabolism   MeSH
• Cannabinoids pharmacology   MeSH
• Mitochondria drug effects   metabolism   MeSH
• Brain drug effects   metabolism   MeSH
• Swine MeSH
• Electron Transport Complex I metabolism   MeSH
• Electron Transport Complex II metabolism   MeSH
• Electron Transport Complex III metabolism   MeSH
• Electron Transport Complex IV metabolism   MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Cannabinoid Receptor Antagonists MeSH
• Citrate (si)-Synthase MeSH
• Cannabinoids MeSH
• Electron Transport Complex I MeSH
• Electron Transport Complex II MeSH
• Electron Transport Complex III MeSH
• Electron Transport Complex IV MeSH