Advertisement

Molecular Neurobiology

, Volume 54, Issue 8, pp 5894–5904 | Cite as

In Vitro Effects of Cognitives and Nootropics on Mitochondrial Respiration and Monoamine Oxidase Activity

  • Namrata Singh
  • Jana HroudováEmail author
  • Zdeněk Fišar
Article

Abstract

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 Nootropics Mitochondrial respiration Monoamine oxidase Reactive oxygen species 

Notes

Acknowledgments

Supported by International Post-Doc Research Fund of Charles University, by project PRVOUK-P26/LF1/4 given by Charles University and by grants AZV 15-28967A and 15-28616A, Ministry of Health, Czech Republic. Authors are grateful to Mr. Zdeněk Hanuš for his technical assistance.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Zheng H, Fridkin M, Youdim MB (2012) Novel chelators targeting cell cycle arrest, acetylcholinesterase, and monoamine oxidase for Alzheimer’s therapy. Curr Drug Targets 13(8):1089–1106CrossRefPubMedGoogle Scholar
  2. 2.
    Hroudová J, Singh N, Fišar Z, Ghosh KK (2016) Progress in drug development for Alzheimer’s disease: an overview in relation to mitochondrial energy metabolism. Eur J Med Chem 121:774–784. doi: 10.1016/j.ejmech.2016.03.084 CrossRefPubMedGoogle Scholar
  3. 3.
    Zemek F, Drtinova L, Nepovimova E, Sepsova V, Korabecny J, Klimes J, Kuca K (2014) Outcomes of Alzheimer’s disease therapy with acetylcholinesterase inhibitors and memantine. Expert Opin Drug Saf 13(6):759–774. doi: 10.1517/14740338.2014.914168 PubMedGoogle Scholar
  4. 4.
    Nieoullon A (2010) Acetylcholinesterase inhibitors in Alzheimer’s disease: further comments on their mechanisms of action and therapeutic consequences. Psychol Neuropsychiatrie du vieillissement 8(2):123–131. doi: 10.1684/pnv.2010.0208 Google Scholar
  5. 5.
    Soukup O, Jun D, Zdarova-Karasova J, Patocka J, Musilek K, Korabecny J, Krusek J, Kaniakova M, Sepsova V, Mandikova J, Trejtnar F, Pohanka M, Drtinova L, Pavlik M, Tobin G, Kuca K (2013) A resurrection of 7-MEOTA: a comparison with tacrine. Curr Alzheim Res 10(8):893–906CrossRefGoogle Scholar
  6. 6.
    Korabecny J, Musilek K, Holas O, Nepovimova E, Jun D, Zemek F, Opletalova V, Patocka J, Dohnal V, Nachon F, Hroudova J, Fisar Z, Kuca K (2010) Synthesis and in vitro evaluation of N-(Bromobut-3-en-2-yl)-7-methoxy-1,2,3,4-tetrahydroacridin-9-amine as a cholinesterase inhibitor with regard to Alzheimer’s disease treatment. Mol (Basel, Switzerland) 15(12):8804–8812. doi: 10.3390/molecules15128804 CrossRefGoogle Scholar
  7. 7.
    Korabecny J, Musilek K, Holas O, Binder J, Zemek F, Marek J, Pohanka M, Opletalova V, Dohnal V, Kuca K (2010) Synthesis and in vitro evaluation of N-alkyl-7-methoxytacrine hydrochlorides as potential cholinesterase inhibitors in Alzheimer disease. Bioorg Med Chem Lett 20(20):6093–6095. doi: 10.1016/j.bmcl.2010.08.044 CrossRefPubMedGoogle Scholar
  8. 8.
    Arias E, Gallego-Sandin S, Villarroya M, Garcia AG, Lopez MG (2005) Unequal neuroprotection afforded by the acetylcholinesterase inhibitors galantamine, donepezil, and rivastigmine in SH-SY5Y neuroblastoma cells: role of nicotinic receptors. J Pharmacol Exp Ther 315(3):1346–1353. doi: 10.1124/jpet.105.090365 CrossRefPubMedGoogle Scholar
  9. 9.
    Ye CY, Lei Y, Tang XC, Zhang HY (2015) Donepezil attenuates Abeta-associated mitochondrial dysfunction and reduces mitochondrial Abeta accumulation in vivo and in vitro. Neuropharmacology. doi: 10.1016/j.neuropharm.2015.02.020 PubMedCentralGoogle Scholar
  10. 10.
    Lipton SA (2004) Paradigm shift in NMDA receptor antagonist drug development: molecular mechanism of uncompetitive inhibition by memantine in the treatment of Alzheimer’s disease and other neurologic disorders. J Alzheimer’s Dis : JAD 6(6 Suppl):S61–S74PubMedGoogle Scholar
  11. 11.
    Sabbagh MN, Shill HA (2010) Latrepirdine, a potential novel treatment for Alzheimer’s disease and Huntington’s chorea. Curr Opin Invest Drugs (London, England : 2000) 11(1):80–91Google Scholar
  12. 12.
    Weisova P, Alvarez SP, Kilbride SM, Anilkumar U, Baumann B, Jordan J, Bernas T, Huber HJ, Dussmann H, Prehn JH (2013) Latrepirdine is a potent activator of AMP-activated protein kinase and reduces neuronal excitability. Transl Psychiatry 3:e317. doi: 10.1038/tp.2013.92 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Kurz C, Ungerer I, Lipka U, Kirr S, Schutt T, Eckert A, Leuner K, Muller WE (2010) The metabolic enhancer piracetam ameliorates the impairment of mitochondrial function and neurite outgrowth induced by beta-amyloid peptide. Br J Pharmacol 160(2):246–257. doi: 10.1111/j.1476-5381.2010.00656.x CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Keil U, Scherping I, Hauptmann S, Schuessel K, Eckert A, Muller WE (2006) Piracetam improves mitochondrial dysfunction following oxidative stress. Br J Pharmacol 147(2):199–208. doi: 10.1038/sj.bjp.0706459 CrossRefPubMedGoogle Scholar
  15. 15.
    Zhang HY (2012) New insights into huperzine A for the treatment of Alzheimer’s disease. Acta Pharmacol Sin 33(9):1170–1175. doi: 10.1038/aps.2012.128 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Mattiasson G (2004) Analysis of mitochondrial generation and release of reactive oxygen species. Cytom Part A: J Int Soc Anal Cytol 62(2):89–96. doi: 10.1002/cyto.a.20089 CrossRefGoogle Scholar
  17. 17.
    Hirst J, King MS, Pryde KR (2008) The production of reactive oxygen species by complex I. Biochem Soc Trans 36(Pt 5):976–980. doi: 10.1042/bst0360976 CrossRefPubMedGoogle Scholar
  18. 18.
    Drose S, Brandt U (2008) The mechanism of mitochondrial superoxide production by the cytochrome bc1 complex. J Biol Chem 283(31):21649–21654. doi: 10.1074/jbc.M803236200 CrossRefPubMedGoogle Scholar
  19. 19.
    Leuner K, Schutt T, Kurz C, Eckert SH, Schiller C, Occhipinti A, Mai S, Jendrach M, Eckert GP, Kruse SE, Palmiter RD, Brandt U, Drose S, Wittig I, Willem M, Haass C, Reichert AS, Muller WE (2012) Mitochondrion-derived reactive oxygen species lead to enhanced amyloid beta formation. Antioxid Redox Signal 16(12):1421–1433. doi: 10.1089/ars.2011.4173 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Fišar Z, Hroudová J, Raboch J (2010) Inhibition of monoamine oxidase activity by antidepressants and mood stabilizers. Neuro Endocrinol Lett 31(5):645–656PubMedGoogle Scholar
  21. 21.
    Fisar Z (2010) Inhibition of monoamine oxidase activity by cannabinoids. Naunyn Schmiedeberg’s Arch Pharmacol 381(6):563–572. doi: 10.1007/s00210-010-0517-6 CrossRefGoogle Scholar
  22. 22.
    Fišar Z, Hroudová J, Korábečný J, Musílek K, Kuča K (2011) In vitro effects of acetylcholinesterase reactivators on monoamine oxidase activity. Toxicol Lett 201(2):176–180. doi: 10.1016/j.toxlet.2010.12.023 CrossRefPubMedGoogle Scholar
  23. 23.
    Pinna G, Broedel O, Eravci M, Stoltenburg-Didinger G, Plueckhan H, Fuxius S, Meinhold H, Baumgartner A (2003) Thyroid hormones in the rat amygdala as common targets for antidepressant drugs, mood stabilizers, and sleep deprivation. Biol Psychiatry 54(10):1049–1059CrossRefPubMedGoogle Scholar
  24. 24.
    Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193(1):265–275PubMedGoogle Scholar
  25. 25.
    Folbergrová J, Jesina P, Haugvicová R, Lisý V, Houstek J (2010) Sustained deficiency of mitochondrial complex I activity during long periods of survival after seizures induced in immature rats by homocysteic acid. Neurochem Int 56(3):394–403. doi: 10.1016/j.neuint.2009.11.011 CrossRefPubMedGoogle Scholar
  26. 26.
    Hroudova J, Fisar Z (2010) Activities of respiratory chain complexes and citrate synthase influenced by pharmacologically different antidepressants and mood stabilizers. Neuro Endocrinol Lett 31(3):336–342PubMedGoogle Scholar
  27. 27.
    Trounce IA, Kim YL, Jun AS, Wallace DC (1996) Assessment of mitochondrial oxidative phosphorylation in patient muscle biopsies, lymphoblasts, and transmitochondrial cell lines. Methods Enzymol 264:484–509CrossRefPubMedGoogle Scholar
  28. 28.
    Rustin P, Chretien D, Bourgeron T, Gerard B, Rotig A, Saudubray JM, Munnich A (1994) Biochemical and molecular investigations in respiratory chain deficiencies. Clin Chim Acta; Int J Clin Chem 228(1):35–51CrossRefGoogle Scholar
  29. 29.
    Srere PA (1969) Citrate synthase: [EC 4.1.3.7 citrate oxaloacetate-lyase (CoA acetylating)]. Methods Enzymol 13:3–11CrossRefGoogle Scholar
  30. 30.
    Hroudová J, Fišar Z (2012) In vitro inhibition of mitochondrial respiratory rate by antidepressants. Toxicol Lett 213(3):345–352. doi: 10.1016/j.toxlet.2012.07.017 CrossRefPubMedGoogle Scholar
  31. 31.
    Pesta D, Gnaiger E (2012) High-resolution respirometry: OXPHOS protocols for human cells and permeabilized fibers from small biopsies of human muscle. Methods Mol Biol (Clifton, NJ) 810:25–58. doi: 10.1007/978-1-61779-382-0_3 CrossRefGoogle Scholar
  32. 32.
    Ekstedt B (1976) Substrate specificity of the different forms of monoamine oxidase in rat liver mitochondria. Biochem Pharmacol 25(10):1133–1138CrossRefPubMedGoogle Scholar
  33. 33.
    Egashira T, Takayama F, Yamanaka Y (1999) The inhibition of monoamine oxidase activity by various antidepressants: differences found in various mammalian species. Jpn J Pharmacol 81(1):115–121CrossRefPubMedGoogle Scholar
  34. 34.
    Liu Y, Fiskum G, Schubert D (2002) Generation of reactive oxygen species by the mitochondrial electron transport chain. J Neurochem 80(5):780–787CrossRefPubMedGoogle Scholar
  35. 35.
    Ross T, Szczepanek K, Bowler E, Hu Y, Larner A, Lesnefsky EJ, Chen Q (2013) Reverse electron flow-mediated ROS generation in ischemia-damaged mitochondria: role of complex I inhibition vs. depolarization of inner mitochondrial membrane. Biochim Biophys Acta 1830(10):4537–4542. doi: 10.1016/j.bbagen.2013.05.035 CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Hroudová J, Fišar Z, Korábečný J, Kuča K (2011) In vitro effects of acetylcholinesterase inhibitors and reactivators on complex I of electron transport chain. Neuro Endocrinol Lett 32(3):259–263PubMedGoogle Scholar
  37. 37.
    McAllister J, Ghosh S, Berry D, Park M, Sadeghi S, Wang KX, Parker WD, Swerdlow RH (2008) Effects of memantine on mitochondrial function. Biochem Pharmacol 75(4):956–964. doi: 10.1016/j.bcp.2007.10.019 CrossRefPubMedGoogle Scholar
  38. 38.
    Casademont J, Miro O, Rodriguez-Santiago B, Viedma P, Blesa R, Cardellach F (2003) Cholinesterase inhibitor rivastigmine enhance the mitochondrial electron transport chain in lymphocytes of patients with Alzheimer’s disease. In: J Neurol Sci, vol 206. vol 1. Netherlands, pp 23–26Google Scholar
  39. 39.
    Stockburger C, Kurz C, Koch KA, Eckert SH, Leuner K, Muller WE (2013) Improvement of mitochondrial function and dynamics by the metabolic enhancer piracetam. Biochem Soc Trans 41(5):1331–1334. doi: 10.1042/bst20130054 CrossRefPubMedGoogle Scholar
  40. 40.
    Ustyugov A, Shevtsova E, Bachurin S (2015) Novel sites of neuroprotective action of Dimebon (latrepirdine). Mol Neurobiol. doi: 10.1007/s12035-015-9249-4 PubMedGoogle Scholar
  41. 41.
    Wang L, Esteban G, Ojima M, Bautista-Aguilera OM, Inokuchi T, Moraleda I, Iriepa I, Samadi A, Youdim MB, Romero A, Soriano E, Herrero R, Fernandez Fernandez AP, Ricardo Martinez M, Marco-Contelles J, Unzeta M (2014) Donepezil + propargylamine +8-hydroxyquinoline hybrids as new multifunctional metal-chelators, ChE and MAO inhibitors for the potential treatment of Alzheimer’s disease. Eur J Med Chem 80:543–561. doi: 10.1016/j.ejmech.2014.04.078 CrossRefPubMedGoogle Scholar
  42. 42.
    Lu C, Zhou Q, Yan J, Du Z, Huang L, Li X (2013) A novel series of tacrine-selegiline hybrids with cholinesterase and monoamine oxidase inhibition activities for the treatment of Alzheimer’s disease. Eur J Med Chem 62:745–753. doi: 10.1016/j.ejmech.2013.01.039 CrossRefPubMedGoogle Scholar
  43. 43.
    Shadurskaia SK, Khomenko AI, Pereverzev VA, Balaklevskii AI (1986) Neuromediator mechanisms of the effect of the antihistamine agent dimebone on the brain. Biull Eksp Biol Med 101(6):700–702PubMedGoogle Scholar
  44. 44.
    Stancheva SL, Alova LG (1988) Effect of centrophenoxine, piracetam and aniracetam on the monoamine oxidase activity in different brain structures of rats. Farmakol Toksikol 51(3):16–18PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Department of Psychiatry, First Faculty of MedicineCharles University and General University Hospital in PraguePrague 2Czech Republic

Personalised recommendations