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

Hafsa Amat-Ur-Rasool,Wayne G Carter,Shahida Hasnain,Mehboob Ahmed

doi:10.3390/brainsci11020184

Hafsa Amat-Ur-Rasool, Wayne G Carter + Show 2 more

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https://doi.org/10.3390/brainsci11020184

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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.

Highlights

50 million people globally suffer from dementia and the number is expected to triple by 2050 [1]
(DTNB), all-trans-retinoic acid, thiazolyl blue tetrazolium bromide (MTT), isopropanol, dimethyl sulfoxide (DMSO), and the drugs donepezil hydrochloride, MW = 415.95 g/mol; tacrine hydrochloride, MW = 234.72; berberine hydrochloride, MW = 371.82 g/mol; and galantamine hydrobromide, MW = 368.27 g/mol, were all purchased from Sigma-Aldrich (Poole, UK)
The inhibition curves showed that the potency of the drugs to inhibit AChE was in the order: donepezil > tacrine > berberine > galantamine for both the human (h) and Torpedo californica enzymes

Summary

Introduction

50 million people globally suffer from dementia and the number is expected to triple by 2050 [1]. A reduction of signaling from the neurotransmitter acetylcholine (ACh) led to the concept of a “cholinergic hypothesis” to explain some of the cognitive deficits experienced by AD patients [8,9]. This cholinergic signaling decline provides the basis for the current first-line drug treatment for mild-to-moderate AD: employment of cholinesterase inhibitors (ChEIs) such as donepezil, rivastigmine, and galantamine [10,11,12]. This (reversible) inhibition of AChE within the central nervous system (CNS) is an attempt to prolong ACh signaling

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