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.

• Klíčová slova
• ATP, antidepressants, mitochondrial respiration, monoamine oxidase, oxidative phosphorylation, reactive oxygen species,
• Publikační typ
• časopisecké články MeSH

Mitochondrial dysfunction is an important cellular hallmark of aging and neurodegeneration. Platelets are a useful model to study the systemic manifestations of mitochondrial dysfunction. To evaluate the age dependence of mitochondrial parameters, citrate synthase activity, respiratory chain complex activity, and oxygen consumption kinetics were assessed. The effect of cognitive impairment was examined by comparing the age dependence of mitochondrial parameters in healthy individuals and those with neuropsychiatric disease. The study found a significant negative slope of age-dependence for both the activity of individual mitochondrial enzymes (citrate synthase and complex II) and parameters of mitochondrial respiration in intact platelets (routine respiration, maximum capacity of electron transport system, and respiratory rate after complex I inhibition). However, there was no significant difference in the age-related changes of mitochondrial parameters between individuals with and without cognitive impairment. These findings highlight the potential of measuring mitochondrial respiration in intact platelets as a means to assess age-related mitochondrial dysfunction. The results indicate that drugs and interventions targeting mitochondrial respiration may have the potential to slow down or eliminate certain aging and neurodegenerative processes. Mitochondrial respiration in platelets holds promise as a biomarker of aging, irrespective of the degree of cognitive impairment.

• Klíčová slova
• aging, cognitive decline, mitochondria, mitochondrial respiration, neurodegenerative disease, neuroinflammation, neuroplasticity, oxidative stress, platelet, respiratory chain complex,
• Publikační typ
• časopisecké články MeSH

This determination of the mitochondrial effect of pharmacologically different antidepressants (agomelatine, ketamine and vortioxetine) was evaluated and quantified in vitro in pig brain-isolated mitochondria. We measured the activity of mitochondrial complexes, citrate synthase, malate dehydrogenase and monoamine oxidase, and the mitochondrial respiratory rate. Total hydrogen peroxide production and ATP production were assayed. The most potent inhibitor of all mitochondrial complexes and complex I-linked respiration was vortioxetine. Agomelatine and ketamine inhibited only complex IV activity. None of the drugs affected complex II-linked respiration, citrate synthase or malate dehydrogenase activity. Hydrogen peroxide production was mildly increased by agomelatine, which might contribute to increased oxidative damage and adverse effects at high drug concentrations. Vortioxetine significantly reduced hydrogen peroxide concentrations, which might suggest antioxidant mechanism activation. All tested antidepressants were partial MAO-A inhibitors, which might contribute to their antidepressant effect. We observed vortioxetine-induced MAO-B inhibition, which might be linked to decreased hydrogen peroxide formation and contribute to its procognitive and neuroprotective effects. Mitochondrial dysfunction could be linked to the adverse effects of vortioxetine, as vortioxetine is the most potent inhibitor of mitochondrial complexes and complex I-linked respiration. Clarifying the molecular interaction between drugs and mitochondria is important to fully understand their mechanism of action and the connection between their mechanisms and their therapeutic and/or adverse effects.

• Klíčová slova
• ATP, agomelatine, antidepressants, ketamine, mitochondrial respiration, monoamine oxidase, oxidative phosphorylation, reactive oxygen species, vortioxetine,
• MeSH
• antidepresiva farmakologie   MeSH
• citrátsynthasa MeSH
• ketamin * farmakologie   MeSH
• malátdehydrogenasa MeSH
• monoaminoxidasa MeSH
• peroxid vodíku MeSH
• prasata MeSH
• respirační komplex I MeSH
• vortioxetin farmakologie   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• agomelatine MeSH Prohlížeč
• antidepresiva MeSH
• citrátsynthasa MeSH
• ketamin * MeSH
• malátdehydrogenasa MeSH
• monoaminoxidasa MeSH
• peroxid vodíku MeSH
• respirační komplex I MeSH
• vortioxetin 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.

• Klíčová slova
• Cognitives, Mitochondrial respiration, Monoamine oxidase, Nootropics, Reactive oxygen species,
• MeSH
• Alzheimerova nemoc metabolismus   MeSH
• cholinesterasové inhibitory farmakologie   MeSH
• donepezil MeSH
• galantamin metabolismus   MeSH
• indany farmakologie   MeSH
• kognice účinky léků   MeSH
• memantin farmakologie   MeSH
• mitochondrie účinky léků   metabolismus   MeSH
• monoaminoxidasa účinky léků   metabolismus   MeSH
• mozek účinky léků   metabolismus   MeSH
• nootropní látky farmakologie   MeSH
• piperidiny farmakologie   MeSH
• prasata MeSH
• rivastigmin farmakologie   MeSH
• spotřeba kyslíku účinky léků   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cholinesterasové inhibitory MeSH
• donepezil MeSH
• galantamin MeSH
• indany MeSH
• memantin MeSH
• monoaminoxidasa MeSH
• nootropní látky MeSH
• piperidiny MeSH
• rivastigmin 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
• antagonisté kanabinoidních receptorů farmakologie   MeSH
• citrátsynthasa metabolismus   MeSH
• kanabinoidy farmakologie   MeSH
• mitochondrie účinky léků   metabolismus   MeSH
• mozek účinky léků   metabolismus   MeSH
• prasata MeSH
• respirační komplex I metabolismus   MeSH
• respirační komplex II metabolismus   MeSH
• respirační komplex III metabolismus   MeSH
• respirační komplex IV metabolismus   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antagonisté kanabinoidních receptorů MeSH
• citrátsynthasa MeSH
• kanabinoidy MeSH
• respirační komplex I MeSH
• respirační komplex II MeSH
• respirační komplex III MeSH
• respirační komplex IV MeSH