-
Something wrong with this record ?
Effects of Novel Tacrine Derivatives on Mitochondrial Energy Metabolism and Monoamine Oxidase Activity-In Vitro Study
J. Hroudová, T. Nováková, J. Korábečný, D. Maliňák, L. Górecki, Z. Fišar
Language English Country United States
Document type Journal Article
Grant support
17-07585Y
Grantová Agentura České Republiky
NLK
ProQuest Central
from 1997-02-01 to 1 year ago
Medline Complete (EBSCOhost)
from 2010-02-01 to 1 year ago
Health & Medicine (ProQuest)
from 1997-02-01 to 1 year ago
Psychology Database (ProQuest)
from 1997-02-01 to 1 year ago
- 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
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.
References provided by Crossref.org
- 000
- 00000naa a2200000 a 4500
- 001
- bmc22004586
- 003
- CZ-PrNML
- 005
- 20220127145135.0
- 007
- ta
- 008
- 220113s2021 xxu f 000 0|eng||
- 009
- AR
- 024 7_
- $a 10.1007/s12035-020-02172-1 $2 doi
- 035 __
- $a (PubMed)33089424
- 040 __
- $a ABA008 $b cze $d ABA008 $e AACR2
- 041 0_
- $a eng
- 044 __
- $a xxu
- 100 1_
- $a Hroudová, Jana $u Department of Psychiatry, General University Hospital in Prague, First Faculty of Medicine, Charles University, Ke Karlovu 11, 120 00, Prague 2, Czech Republic. hroudova.jana@gmail.com $u Institute of Pharmacology, General University Hospital in Prague, First Faculty of Medicine, Charles University, Albertov 4, 128 00, Prague 2, Czech Republic. hroudova.jana@gmail.com
- 245 10
- $a Effects of Novel Tacrine Derivatives on Mitochondrial Energy Metabolism and Monoamine Oxidase Activity-In Vitro Study / $c J. Hroudová, T. Nováková, J. Korábečný, D. Maliňák, L. Górecki, Z. Fišar
- 520 9_
- $a 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.
- 650 _2
- $a Alzheimerova nemoc $x farmakoterapie $7 D000544
- 650 _2
- $a zvířata $7 D000818
- 650 _2
- $a buněčné dýchání $x účinky léků $7 D019069
- 650 _2
- $a respirační komplex II $x metabolismus $7 D042963
- 650 12
- $a energetický metabolismus $x účinky léků $7 D004734
- 650 _2
- $a mitochondrie $x účinky léků $x enzymologie $x metabolismus $7 D008928
- 650 _2
- $a monoaminoxidasa $x metabolismus $7 D008995
- 650 _2
- $a inhibitory MAO $x farmakologie $7 D008996
- 650 _2
- $a prasata $7 D013552
- 650 _2
- $a takrin $x chemie $x farmakologie $7 D013619
- 655 _2
- $a časopisecké články $7 D016428
- 700 1_
- $a Nováková, Tereza $u Department of Psychiatry, General University Hospital in Prague, First Faculty of Medicine, Charles University, Ke Karlovu 11, 120 00, Prague 2, Czech Republic
- 700 1_
- $a Korábečný, Jan $u Biomedical Research Centre, University Hospital Hradec Kralove, Sokolská 581, 500 05, Hradec Králové, Czech Republic $u Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Třebešská 1575, 500 01, Hradec Králové, Czech Republic
- 700 1_
- $a Maliňák, Dávid $u Department of Psychiatry, General University Hospital in Prague, First Faculty of Medicine, Charles University, Ke Karlovu 11, 120 00, Prague 2, Czech Republic $u Biomedical Research Centre, University Hospital Hradec Kralove, Sokolská 581, 500 05, Hradec Králové, Czech Republic
- 700 1_
- $a Górecki, Lukáš $u Department of Psychiatry, General University Hospital in Prague, First Faculty of Medicine, Charles University, Ke Karlovu 11, 120 00, Prague 2, Czech Republic $u Biomedical Research Centre, University Hospital Hradec Kralove, Sokolská 581, 500 05, Hradec Králové, Czech Republic
- 700 1_
- $a Fišar, Zdeněk $u Department of Psychiatry, General University Hospital in Prague, First Faculty of Medicine, Charles University, Ke Karlovu 11, 120 00, Prague 2, Czech Republic
- 773 0_
- $w MED00005280 $t Molecular neurobiology $x 1559-1182 $g Roč. 58, č. 3 (2021), s. 1102-1113
- 856 41
- $u https://pubmed.ncbi.nlm.nih.gov/33089424 $y Pubmed
- 910 __
- $a ABA008 $b sig $c sign $y p $z 0
- 990 __
- $a 20220113 $b ABA008
- 991 __
- $a 20220127145131 $b ABA008
- 999 __
- $a ok $b bmc $g 1751900 $s 1155735
- BAS __
- $a 3
- BAS __
- $a PreBMC
- BMC __
- $a 2021 $b 58 $c 3 $d 1102-1113 $e 20201022 $i 1559-1182 $m Molecular neurobiology $n Mol Neurobiol $x MED00005280
- GRA __
- $a 17-07585Y $p Grantová Agentura České Republiky
- LZP __
- $a Pubmed-20220113
