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Anti-Cholinesterase Combination Drug Therapy as a Potential Treatment for Alzheimer’s Disease

Amat-ur-Rasool, Hafsa; Ahmed, Mehboob; Hasnain, Shahida; Carter, Wayne G.

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Authors

Hafsa Amat-ur-Rasool

Mehboob Ahmed

Shahida Hasnain



Abstract

Alzheimer’s disease (AD) is a burgeoning social and healthcare problem. Cholinesterase inhibitors (ChEIs) are employed for symptomatic treatment of AD, but often elicit adverse drug reactions (ADRs). Herein, the potency of the ChEIs, donepezil, tacrine, berberine, and galantamine to inhibit human or Torpedo californica acetylcholinesterase (tcAChE) proteins were evaluated. The efficacy of dual-drug combinations to inhibit human AChE directly and within differentiated neurons was also quantified. ChEI potency was in the order: donepezil > tacrine > berberine > galantamine for both AChEs. Dual-drug combinations of berberine and tacrine (BerTac), berberine and galantamine (BerGal), and tacrine and donepezil (TacDon) all produced synergistic outcomes for AChE inhibition. Donepezil and berberine (DonBer) and tacrine and galantamine (TacGal) elicited antagonistic responses. Donepezil and galantamine (DonGal) was synergistic for human AChE but antagonistic for tcAChE. After application of dual-drug combinations to neuronal cells, BerTac, BerGal, DonGal, and DonBer all showed synergistic inhibition of AChE, TacDon additive, and TacGal antagonistic effects. BerGal produced the most potent synergism and reduced total drug dose by 72%. Individual ChEIs or dual-drug combinations were relatively non-toxic to neuronal cells, and only reduced cell viability at concentrations two–three orders of magnitude greater than that required to inhibit AChE. In summary, dual-drug combinations of ChEIs potentially represent a novel means of AD patient treatment, with reduced and more cost-effective drug dosing, and lowered likelihood of ADRs.

Citation

Amat-ur-Rasool, H., Ahmed, M., Hasnain, S., & Carter, W. G. (2021). Anti-Cholinesterase Combination Drug Therapy as a Potential Treatment for Alzheimer’s Disease. Brain Sciences, 11(2), Article 184. https://doi.org/10.3390/brainsci11020184

Journal Article Type Article
Acceptance Date Jan 30, 2021
Online Publication Date Feb 2, 2021
Publication Date Feb 2, 2021
Deposit Date Feb 3, 2021
Publicly Available Date Mar 28, 2024
Journal Brain Sciences
Publisher MDPI
Peer Reviewed Peer Reviewed
Volume 11
Issue 2
Article Number 184
DOI https://doi.org/10.3390/brainsci11020184
Keywords Alzheimer’s disease; cholinesterase inhibitors; drug synergism
Public URL https://nottingham-repository.worktribe.com/output/5291021
Publisher URL https://www.mdpi.com/2076-3425/11/2/184

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