Competitive Inhibition and Synergistic Effects of Nutraceutical and Metabolite Molecules on Anti-Acetylcholinesterase Activity

Year 2024, Volume: 11 Issue: 2, 575 - 584

Munteha Girgin Shirin Tarbiat Sevim Işık Nigar Kantarcı-carsıbası

https://doi.org/10.18596/jotcsa.1367877

Abstract

The rapidly increasing prevalence of Alzheimer's disease (AD) poses a significant global public health threat. While medications such as Donepezil, Galantamine, and Rivastigmine are used, their serious side effects and limited healing fail to provide a definite cure. Consequently, combination therapies are being explored to enhance the efficacy of existing drugs. This study aims to evaluate the anti-acetylcholinesterase activities of previously identified nutraceutical and metabolite compounds, namely Queuine, Etoperidone, and Thiamine. Combined use of Queuine with Donepezil, Etoperidone, and Thiamine on acetylcholinesterase enzyme inhibition is also evaluated. The effects of the drug combinations on cell viability and acetylcholinesterase inhibition were investigated by using safe doses determined for each drug. The cytotoxic effect of drug combinations was investigated on the SH-SY5Y cell line using the RTCA method. All the individual or drug combinations were non-toxic to neuronal cells. Anti-acetylcholinesterase activities were estimated by Ellman’s method yielding the inhibition percentages as 70%, 61%, 45%, and 51% for Donepezil, Etoperidone, Queuine, and Thiamine, respectively. When drug combinations were analyzed, competitive inhibition resulted for Queuine+Donepezil and Queuine+Thiamine, the enzyme inhibition percentages being diminished to 47% and 21%, respectively. A significant synergistic effect was observed for Queuine+Etoperidone with the highest inhibition of 74%. This study provides the first evidence of the nutraceutical molecule Queuine's impact on acetylcholinesterase inhibition and the synergistic effect of Queuine and Etoperidone as a potent drug combination surpassing the effectiveness of Donepezil. Queuine and Etoperidone synergism may serve as a potential AD treatment by further in vivo validations.

Keywords

Alzheimer's Disease, Acetylcholinesterase (AChE), Ellman assay, Queuine, Etoperidone

References

• 1. Castro A, Martinez A. Targeting Beta-Amyloid Pathogenesis Through Acetylcholinesterase Inhibitors. Curr Pharm Des [Internet]. 2006 Nov 1;12(33):4377–87. Available from: <URL>.
• 2. Colovic MB, Krstic DZ, Lazarevic-Pasti TD, Bondzic AM, Vasic VM. Acetylcholinesterase Inhibitors: Pharmacology and Toxicology. Curr Neuropharmacol [Internet]. 2013;11(3):315–35. Available from: <URL>.
• 3. Breijyeh Z, Karaman R. Comprehensive Review on Alzheimer’s Disease: Causes and Treatment. Molecules [Internet]. 2020 Dec 8;25(24):5789. Available from: <URL>.
• 4. Johnson G, Moore S. The Peripheral Anionic Site of Acetylcholinesterase: Structure, Functions and Potential Role in Rational Drug Design. Curr Pharm Des [Internet]. 2006 Jan 1;12(2):217–25. Available from: <URL>.
• 5. Piazzi L, Rampa A, Bisi A, Gobbi S, Belluti F, Cavalli A, et al. 3-(4-{[Benzyl(methyl)amino]methyl}phenyl)-6,7-dimethoxy-2 H -2-chromenone (AP2238) Inhibits Both Acetylcholinesterase and Acetylcholinesterase-Induced β-Amyloid Aggregation:  A Dual Function Lead for Alzheimer’s Disease Therapy. J Med Chem [Internet]. 2003 Jun 1;46(12):2279–82. Available from: <URL>.
• 6. Zhang Y, Li P, Feng J, Wu M. Dysfunction of NMDA receptors in Alzheimer’s disease. Neurol Sci [Internet]. 2016 Jul 12;37(7):1039–47. Available from: <URL>.
• 7. Penke B, Bogár F, Fülöp L. β-Amyloid and the Pathomechanisms of Alzheimer’s Disease: A Comprehensive View. Molecules [Internet]. 2017 Oct 10;22(10):1692. Available from: <URL>.
• 8. Balkrishna A, Pokhrel S, Tomer M, Verma S, Kumar A, Nain P, et al. Anti-Acetylcholinesterase Activities of Mono-Herbal Extracts and Exhibited Synergistic Effects of the Phytoconstituents: A Biochemical and Computational Study. Molecules [Internet]. 2019 Nov 18;24(22):4175. Available from: <URL>.
• 9. Khan H, Marya, Amin S, Kamal MA, Patel S. Flavonoids as acetylcholinesterase inhibitors: Current therapeutic standing and future prospects. Biomed Pharmacother [Internet]. 2018 May 1;101:860–70. Available from: <URL>.
• 10. Abdul Manap AS, Wei Tan AC, Leong WH, Yin Chia AY, Vijayabalan S, Arya A, et al. Synergistic Effects of Curcumin and Piperine as Potent Acetylcholine and Amyloidogenic Inhibitors With Significant Neuroprotective Activity in SH-SY5Y Cells via Computational Molecular Modeling and in vitro Assay. Front Aging Neurosci [Internet]. 2019 Aug 27;11:471888. Available from: <URL>.
• 11. Chiu H-F, Venkatakrishnan K, Wang C-K. The role of nutraceuticals as a complementary therapy against various neurodegenerative diseases: A mini-review. J Tradit Complement Med [Internet]. 2020 Sep 1;10(5):434–9. Available from: <URL>.
• 12. Tarbiat S, Unver D, Tuncay S, Isik S, Yeman KB, Mohseni AR. Neuroprotective effects of Cubebin and Hinokinin lignan fractions of Piper cubeba fruit in Alzheimer’s disease in vitro model. Turkish J Biochem [Internet]. 2023 Jul 19;48(3):303–10. Available from: <URL>.
• 13. Choi RCY, Zhu JTT, Yung AWY, Lee PSC, Xu SL, Guo AJY, et al. Synergistic Action of Flavonoids, Baicalein, and Daidzein in Estrogenic and Neuroprotective Effects: A Development of Potential Health Products and Therapeutic Drugs against Alzheimer’s Disease. Evidence-Based Complement Altern Med [Internet]. 2013;2013:1–10. Available from: <URL>.
• 14. Coqueiro A, Fernandes DC, Danuello A, Regasini LO, Cardoso-Lopes EM, Young MCM, et al. Nematostatic activity of isoprenylated guanidine alkaloids from Pterogyne nitens and their interaction with acetylcholinesterase. Exp Parasitol [Internet]. 2023 Jul 1;250:108542. Available from: <URL>.
• 15. Chierrito TPC, Pedersoli-Mantoani S, Roca C, Requena C, Sebastian-Perez V, Castillo WO, et al. From dual binding site acetylcholinesterase inhibitors to allosteric modulators: A new avenue for disease-modifying drugs in Alzheimer’s disease. Eur J Med Chem [Internet]. 2017 Oct 20;139:773–91. Available from: <URL>.
• 16. Amat-ur-Rasool H, Ahmed M, Hasnain S, Carter WG. Anti-Cholinesterase Combination Drug Therapy as a Potential Treatment for Alzheimer’s Disease. Brain Sci [Internet]. 2021 Feb 2;11(2):184. Available from: <URL>.
• 17. Girgin M, Isik S, Kantarci-Carsibasi N. Proposing novel natural compounds against Alzheimer’s disease targeting acetylcholinesterase. Al-Karmalawy AA, editor. PLoS One [Internet]. 2023 Apr 27;18(4):e0284994. Available from: <URL>.
• 18. Gibson GE, Hirsch JA, Fonzetti P, Jordan BD, Cirio RT, Elder J. Vitamin B1 (thiamine) and dementia. Ann N Y Acad Sci [Internet]. 2016 Mar 11;1367(1):21–30. Available from: <URL>.
• 19. Liu D, Ke Z, Luo J. Thiamine Deficiency and Neurodegeneration: the Interplay Among Oxidative Stress, Endoplasmic Reticulum Stress, and Autophagy. Mol Neurobiol [Internet]. 2017 Sep 5;54(7):5440–8. Available from: <URL>.
• 20. Koppel J, Jimenez H, Adrien L, Greenwald BS, Marambaud P, Cinamon E, et al. Haloperidol inactivates AMPK and reduces tau phosphorylation in a tau mouse model of Alzheimer’s disease. Alzheimer’s Dement Transl Res Clin Interv [Internet]. 2016 Jun 21;2(2):121–30. Available from: <URL>.
• 21. Brauer R, Lau WCY, Hayes JF, Man KKC, Osborn DPJ, Howard R, et al. Trazodone use and risk of dementia: A population-based cohort study. Brayne C, editor. PLOS Med [Internet]. 2019 Feb 5;16(2):e1002728. Available from: <URL>.
• 22. Richard P, Kozlowski L, Guillorit H, Garnier P, McKnight NC, Danchin A, et al. Queuine, a bacterial-derived hypermodified nucleobase, shows protection in in vitro models of neurodegeneration. Witt SN, editor. PLoS One [Internet]. 2021 Aug 11;16(8):e0253216. Available from: <URL>.
• 23. Ellman GL, Courtney KD, Andres V, Featherstone RM. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol [Internet]. 1961 Jul 1;7(2):88–95. Available from: <URL>.
• 24. Das JR, Tizabi Y. Additive Protective Effects of Donepezil and Nicotine Against Salsolinol-Induced Cytotoxicity in SH-SY5Y Cells. Neurotox Res [Internet]. 2009 Oct 20;16(3):194–204. Available from: <URL>.
• 25. Tarbiat S, Türütoğlu AS, Ekingen M. Acetylcholinesterase Inhibitory Potential and Antioxidant Activities of Five Cultivars of Rosa Damascena Mill. From Isparta, Turkey. Curr Top Nutraceutical Res [Internet]. 2020;18(4):354–9. Available from: <URL>.
• 26. He F. BCA (Bicinchoninic Acid) Protein Assay. Bio-Protocol [Internet]. 2011;1(5):1–2. Available from: <URL>.
• 27. Lisciani R, Baldini A, Benedetti D, Campana A, Barcellona PS. Acute Cardiovascular toxicity of trazodone, etoperidone and imipramine in rats. Toxicology [Internet]. 1978 Jan 1;10(C):151–8. Available from: <URL>.
• 28. Caldwell GW, Wu WN, Masucci JA. Evaluation of the absorption, excretion and metabolism of [14 C] etoperidone in man. Xenobiotica [Internet]. 2001 Jan 22;31(11):823–39. Available from: <URL>.
• 29. Albert-Gasco H, Smith HL, Alvarez-Castelao B, Swinden D, Halliday M, Janaki-Raman S, et al. Trazodone rescues dysregulated synaptic and mitochondrial nascent translatomes in prion neurodegeneration. bioRxiv [Internet]. 2023 Jun 7; Available from: <URL>.
• 30. Wichniak A, Wierzbicka A, Jarema M. Treatment of insomnia – effect of trazodone and hypnotics on sleep. Psychiatr Pol [Internet]. 2021 Aug 31;55(4):743–55. Available from: <URL>.