Skip to main content

Advertisement

SpringerLink
Log in

Dual monoamine oxidase B and acetylcholine esterase inhibitors for treating movement and cognition deficits in a C. elegans model of Parkinson’s disease

  • Original Research
  • Published:
Medicinal Chemistry Research Aims and scope Submit manuscript

Abstract

Parkinson’s disease (PD) is an age-associated neurodegenerative movement disorder that leads to loss of dopaminergic neurons and motor deficits. Approaches to neuroprotection and symptom management in PD include use of monoamine oxidase B (MAO-B) inhibitors. Many patients with PD also exhibit memory loss in the later stages of disease progression, which is treated with acetylcholine esterase (AChE) inhibitors. We sought to identify a dual-mechanism compound that would inhibit both MAO-B and AChE enzymes. Our screen identified a promising compound (7) with balanced MAO-B (IC50 of 16.83 µM) and AChE inhibition activity (AChE IC50 of 22.04 µM). Application of this compound 7 increased short-term associative memory and significantly prevented 6-hydroxy-dopamine toxicity in dopaminergic neurons in the Caenorhabditis elegans nematode. These findings present a platform for future development of dual-mechanism drugs to treat neurodegenerative diseases such as PD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Galindo MF, Solesio ME, Atienzar-Aroca S, Zamora MJ, Jordan Bueso J. Mitochondrial dynamics and mitophagy in the 6-hydroxydopamine preclinical model of Parkinson’s disease. Parkinson’s Dis. 2012;2012:131058. https://doi.org/10.1155/2012/131058.

    Article  CAS  Google Scholar 

  2. Bernheimer H, Birkmayer W, Hornykiewicz O, Jellinger K, Seitelberger F. Brain dopamine and the syndromes of Parkinson and Huntington. Clinical, morphological and neurochemical correlations. J Neurol Sci. 1973;20:415–55.

    Article  CAS  Google Scholar 

  3. Dardiotis E, Xiromerisiou G, Hadjichristodoulou C, Tsatsakis AM, Wilks MF, Hadjigeorgiou GM. The interplay between environmental and genetic factors in Parkinson’s disease susceptibility: the evidence for pesticides. Toxicology. 2013;307:17–23. https://doi.org/10.1016/j.tox.2012.12.016.

    Article  CAS  PubMed  Google Scholar 

  4. Singleton AB, Farrer MJ, Bonifati V. The genetics of Parkinson’s disease: progress and therapeutic implications. Mov Disord : Off J Mov Disord Soc. 2013;28:14–23. https://doi.org/10.1002/mds.25249.

    Article  CAS  Google Scholar 

  5. Surmeier DJ, Guzman JN, Sanchez-Padilla J, Goldberg JA. What causes the death of dopaminergic neurons in Parkinson’s disease?. Prog brain Res. 2010;183:59–77. https://doi.org/10.1016/S0079-6123(10)83004-3.

    Article  CAS  PubMed  Google Scholar 

  6. Tolleson CM, Fang JY. Advances in the mechanisms of Parkinson’s disease. Discov Med. 2013;15:61–6.

    PubMed  Google Scholar 

  7. Chung SJ, Yoo HS, Lee YH, Sohn YH, Ye BS, Cha J. et al. Minimal parkinsonism in the elderly is associated with striatal dopamine loss and pontine structural damage. Parkinsonism Relat Disord. 2020;81:140–3. https://doi.org/10.1016/j.parkreldis.2020.10.038.

    Article  PubMed  Google Scholar 

  8. Edmondson DE, Binda C, Mattevi A. Structural insights into the mechanism of amine oxidation by monoamine oxidases A and B. Arch Biochem Biophys. 2007;464:269–76. https://doi.org/10.1016/j.abb.2007.05.006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Weinreb O, Amit T, Bar-Am O, Youdim MB. Ladostigil: a novel multimodal neuroprotective drug with cholinesterase and brain-selective monoamine oxidase inhibitory activities for Alzheimer’s disease treatment. Curr Drug Targets. 2012;13:483–94.

    Article  CAS  Google Scholar 

  10. Weinreb O, Amit T, Bar-Am O, Youdim MB. Rasagiline: a novel anti-Parkinsonian monoamine oxidase-B inhibitor with neuroprotective activity. Prog Neurobiol. 2010;92:330–44. https://doi.org/10.1016/j.pneurobio.2010.06.008.

    Article  CAS  PubMed  Google Scholar 

  11. Youdim MB, Bakhle YS. Monoamine oxidase: isoforms and inhibitors in Parkinson’s disease and depressive illness. Br J Pharmacol. 2006;147 Suppl 1:S287–96. https://doi.org/10.1038/sj.bjp.0706464.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Gerlach M, Riederer P, Przuntek H, Youdim MB. MPTP mechanisms of neurotoxicity and their implications for Parkinson’s disease. Eur J Pharmacol. 1991;208:273–86.

    Article  CAS  Google Scholar 

  13. Saura J, Andres N, Andrade C, Ojuel J, Eriksson K, Mahy N. Biphasic and region-specific MAO-B response to aging in normal human brain. Neurobiol Aging. 1997;18:497–507.

    Article  CAS  Google Scholar 

  14. Mahy N, Andres N, Andrade C, Saura J. Age-related changes of MAO-A and -B distribution in human and mouse brain. Neurobiology. 2000;8:47–54.

    CAS  PubMed  Google Scholar 

  15. Geldenhuys WJ, Youdim MB, Carroll RT, Van der Schyf CJ. The emergence of designed multiple ligands for neurodegenerative disorders. Prog Neurobiol. 2011;94:347–59. https://doi.org/10.1016/j.pneurobio.2011.04.010.

    Article  CAS  PubMed  Google Scholar 

  16. Allahtavakoli M, Shabanzadeh AP, Sadr SS, Parviz M, Djahanguiri B. Rosiglitazone, a peroxisome proliferator-activated receptor-gamma ligand, reduces infarction volume and neurological deficits in an embolic model of stroke. Clin Exp Pharmacol Physiol. 2006;33:1052–8. https://doi.org/10.1111/j.1440-1681.2006.04486.x.

    Article  CAS  PubMed  Google Scholar 

  17. Weinstock M, Bejar C, Wang RH, Poltyrev T, Gross A, Finberg JP. et al. TV3326, a novel neuroprotective drug with cholinesterase and monoamine oxidase inhibitory activities for the treatment of Alzheimer’s disease. J Neural Transm Suppl. 2000;60:157–69. https://doi.org/10.1007/978-3-7091-6301-6_10.

    Article  Google Scholar 

  18. Zhang Q, Aldridge GM, Narayanan NS, Anderson SW, Uc EY. Approach to cognitive impairment in Parkinson’s disease. Neurotherapeutics. 2020. https://doi.org/10.1007/s13311-020-00963-x.

  19. Savelieff MG, Nam G, Kang J, Lee HJ, Lee M, Lim MH. Development of multifunctional molecules as potential therapeutic candidates for Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis in the last decade. Chem Rev. 2019;119:1221–322. https://doi.org/10.1021/acs.chemrev.8b00138.

    Article  CAS  PubMed  Google Scholar 

  20. Geldenhuys WJ, Van der Schyf CJ. Rationally designed multi-targeted agents against neurodegenerative diseases. Curr Med Chem. 2013;20:1662–72. https://doi.org/10.2174/09298673113209990112.

    Article  CAS  PubMed  Google Scholar 

  21. Van der Schyf CJ, Geldenhuys WJ. Multimodal drugs and their future for Alzheimer’s and Parkinson’s disease. Int Rev Neurobiol. 2011;100:107–25. https://doi.org/10.1016/B978-0-12-386467-3.00006-6.

    Article  CAS  PubMed  Google Scholar 

  22. Santin Y, Resta J, Parini A, Mialet-Perez J. Monoamine oxidases in age-associated diseases: new perspectives for old enzymes. Ageing Res Rev. 2021;66:101256. https://doi.org/10.1016/j.arr.2021.101256.

    Article  CAS  PubMed  Google Scholar 

  23. Jellinger KA. Neurobiology of cognitive impairment in Parkinson’s disease. Expert Rev Neurother. 2012;12:1451–66. https://doi.org/10.1586/ern.12.131

    Article  CAS  PubMed  Google Scholar 

  24. Kerns EH, Di L. Pharmaceutical profiling in drug discovery. Drug Discov Today. 2003;8:316–23.

    Article  CAS  Google Scholar 

  25. Ploch-Jankowska A, Pentak D. A comprehensive spectroscopic analysis of the ibuprofen binding with human serum albumin, part I. Pharmaceuticals. 2020;13. https://doi.org/10.3390/ph13090205.

  26. Czub MP, Handing KB, Venkataramany BS, Cooper DR, Shabalin IG, Minor W. Albumin-based transport of nonsteroidal anti-inflammatory drugs in mammalian blood plasma. J Med Chem. 2020;63:6847–62. https://doi.org/10.1021/acs.jmedchem.0c00225.

    Article  CAS  PubMed  Google Scholar 

  27. Wishart DS. Improving early drug discovery through ADME modelling: an overview. Drugs R D. 2007;8:349–62. https://doi.org/10.2165/00126839-200708060-00003.

    Article  CAS  PubMed  Google Scholar 

  28. Martinez BA, Caldwell KA, Caldwell GA. C. elegans as a model system to accelerate discovery for Parkinson disease. Curr Opin Genet Dev. 2017;44:102–9. https://doi.org/10.1016/j.gde.2017.02.011.

    Article  CAS  PubMed  Google Scholar 

  29. Geldenhuys WJ, Kochi A, Lin L, Sutariya V, Dluzen DE, Van der Schyf CJ. et al. Methyl yellow: a potential drug scaffold for Parkinson’s disease. Chembiochem. 2014;15:1591–8. https://doi.org/10.1002/cbic.201300770.

    Article  CAS  PubMed  Google Scholar 

  30. Binda C, Aldeco M, Geldenhuys WJ, Tortorici M, Mattevi A, Edmondson DE. Molecular insights into human monoamine oxidase B inhibition by the glitazone anti-diabetes drugs. ACS Med Chem Lett. 2011;3:39–42. https://doi.org/10.1021/ml200196p.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Binda C, Aldeco M, Mattevi A, Edmondson DE. Interactions of monoamine oxidases with the antiepileptic drug zonisamide: specificity of inhibition and structure of the human monoamine oxidase B complex. J Med Chem. 2011;54:909–12. https://doi.org/10.1021/jm101359c.

    Article  CAS  PubMed  Google Scholar 

  32. Joubert J, Foka GB, Repsold BP, Oliver DW, Kapp E, Malan SF. Synthesis and evaluation of 7-substituted coumarin derivatives as multimodal monoamine oxidase-B and cholinesterase inhibitors for the treatment of Alzheimer’s disease. Eur J Med Chem. 2017;125:853–64. https://doi.org/10.1016/j.ejmech.2016.09.041.

    Article  CAS  PubMed  Google Scholar 

  33. Daina A, Michielin O, Zoete V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep. 2017;7:42717. https://doi.org/10.1038/srep42717.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Acharya R, Chacko S, Bose P, Lapenna A, Pattanayak SP. Structure based multitargeted molecular docking analysis of selected furanocoumarins against breast cancer. Sci Rep. 2019;9:15743. https://doi.org/10.1038/s41598-019-52162-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Greeff J, Joubert J, Malan SF, van Dyk S. Antioxidant properties of 4-quinolones and structurally related flavones. Bioorg Med Chem. 2012;20:809–18. https://doi.org/10.1016/j.bmc.2011.11.068.

    Article  CAS  PubMed  Google Scholar 

  36. Al-Baghdadi OB, Prater NI, Van der Schyf CJ, Geldenhuys WJ. Inhibition of monoamine oxidase by derivatives of piperine, an alkaloid from the pepper plant Piper nigrum, for possible use in Parkinson’s disease. Bioorg Med Chem Lett. 2012;22:7183–8. https://doi.org/10.1016/j.bmcl.2012.09.056.

    Article  CAS  PubMed  Google Scholar 

  37. Kauffman A, Parsons L, Stein G, Wills A, Kaletsky R, Murphy C. C. elegans positive butanone learning, short-term, and long-term associative memory assays. J Vis Exp : JoVE. 2011. https://doi.org/10.3791/2490.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This study was funded in part by the Richard Nicely and Glenn and Karen Leppo Parkinson’s Disease Research Funds, the Stark Community Foundation Canton, Ohio, USA, and a grant from the Michael J. Fox Foundation. Additional funding for this work was provided in part by NIH/NIGMS Award Number U54GM104942, WV INBRE P20GM103434 and the WVU Stroke CoBRE NIH grant P20GM109098.

Author information

Author notes

  1. These authors contributed equally: Jacob R. Boos, Ahmed Shubbar

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, WV, USA

    Jacob R Boos & Werner J. Geldenhuys

  2. Department of Neuroscience, School of Medicine, West Virginia University, Morgantown, WV, USA

    Jacob R Boos & Werner J. Geldenhuys

  3. Biomedical Sciences Program, Kent State University, Kent, OH, USA

    Ahmed Shubbar

Authors
  1. Jacob R Boos
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ahmed Shubbar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Werner J. Geldenhuys
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Werner J. Geldenhuys.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Boos, J.R., Shubbar, A. & Geldenhuys, W.J. Dual monoamine oxidase B and acetylcholine esterase inhibitors for treating movement and cognition deficits in a C. elegans model of Parkinson’s disease. Med Chem Res 30, 1166–1174 (2021). https://doi.org/10.1007/s00044-021-02720-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00044-021-02720-x

Keywords

Search

Navigation