Details

Autor(en) / Beteiligte

• Vinklarova, Lucie
• Hroudova, Jana
• Musilek, Kamil
• Benek, Ondrej
• Raboch, Jiri
• Schmidt, Monika
• Fisar, Zdenek
• Hroch, Lukas

Titel

Effects of novel 17[beta]-hydroxysteroid dehydrogenase type 10 inhibitors on mitochondrial respiration

Ist Teil von

• Toxicology letters, 2021-03, Vol.339, p.12

Ort / Verlag

Elsevier B.V

Erscheinungsjahr

2021

Link zum Volltext

Quelle

Elsevier ScienceDirect Journals Complete

Beschreibungen/Notizen

• Keywords Alzheimer's disease; Drug development; Mitochondrial toxicity; Electron transport chain; Monoamine oxidase; 17[beta]-hydroxysteroid dehydrogenase type 10 Highlights * Mitochondrial in vitro effect of 42 novel modulators of 17[beta]-HSD was tested. * Inhibition of complex I-linked respiration occurs at high drug concentration. * Inhibition of complex II-linked respiration was negligible for most molecules. * Most of tested drugs were selective monoamine oxidase type A inhibitors. * Six of the 42 new compounds had minimal effect on mitochondrial function. Mitochondrial enzymes are targets of newly synthesized drugs being tested for the treatment of neurodegenerative disorders, such as Alzheimer's disease (AD). The enzyme 17[beta]-hydroxysteroid dehydrogenase type 10 (HSD10) is a multifunctional mitochondrial protein that is thought to play a role in the pathophysiology of AD and is one of the targets of new potential AD drugs. The in vitro effects of frentizole, riluzole, AG18051, and 42 novel modulators of HSD10 (potential AD drugs) on citrate synthase (CS) activity, monoamine oxidase (MAO) activity, complex I- or complex II-linked mitochondrial respiratory rate, and complex I activity were measured in isolated pig brain mitochondria. Based on their minimal inhibitory effects on the respiratory rate of mitochondria and CS and complex I activity, six novel compounds were selected for further testing. Assuming that inhibition of MAO-B could be a desirable effect of AD drugs, only AG18051 and one new compound met the criteria for MAO-B inhibition with minimal drug-induced effects on mitochondrial respiration. In conclusion, our in vitro screening of mitochondrial effect of novel potential AD drugs has enabled the selection of the most promising molecules for further testing that are relatively safe in terms of drug-induced mitochondrial toxicity. Abbreviations 5-HT, serotonin; A[beta], amyloid beta; AD, Alzheimer's disease; CS, citrate synthase; DMSO, dimethyl sulfoxide; DTNB, 5,5'-dithiobis-(2-nitrobenzoic) acid; ETS, electron transfer system; HSD10, 17[beta]-HSD10, ABAD, 17[beta]-hydroxysteroid dehydrogenase type 10; IC.sub.50, half maximal inhibitory concentration; MAO, monoamine oxidase; MiR05, mitochondrial respiration medium; NADH, nicotinamide adenine dinucleotide; mPTP, mitochondrial permeability transition pore; OXPHOS, oxidative phosphorylation; PEA, phenylethylamine; ROS, reactive oxygen species Author Affiliation: (a) Charles University and General University Hospital in Prague, First Faculty of Medicine, Department of Psychiatry, Ke Karlovu 11, 120 00, Prague 2, Czech Republic (b) University of Hradec Kralove, Faculty of Science, Department of Chemistry, Rokitanskeho 62, 500 03, Hradec Kralove, Czech Republic (c) University Hospital in Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic * Corresponding authors. Article History: Received 24 July 2020; Revised 2 December 2020; Accepted 19 December 2020 Byline: Zdenek Fisar [zfisar@lf1.cuni.cz] (a,*), Kamil Musilek [kamil.musilek@gmail.com] (b,*), Ondrej Benek (b), Lukas Hroch (c), Lucie Vinklarova (b), Monika Schmidt (b), Jana Hroudova (a), Jiri Raboch (a)