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

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.

In Silico Design of Dual-Binding Site Anti-Cholinesterase Phytochemical Heterodimers as Treatment Options for Alzheimer’s Disease

“…Berberine, a natural isoquinoline alkaloid often isolated from the Chinese herb Rhizoma coptidis, displays a plethora of biologically active properties and similar to sanguinarine, can also induce cytotoxicity [68]. Berberine displays relatively potent anti-AChE binding and inhibitory activity, with IC 50 values of approximately 0.3-3 µM, in line with theoretical Kd values [29,37,51,66,67,[69][70][71]. In comparison, berberine is a weaker inhibitor of BuChE with IC 50 values in the range of 3-18 µM (for equine BuChE) [69,70].…”

“…The transient inhibition of AChE via a ChEI monotherapy remains the primary strategy to combat the cholinergic signaling deficit that contributes to the cognitive decline in AD. However, there has been a recent paradigm shift from a single drug, single target approach to the production of drugs with improved efficacy that also simultaneously address multiple components of disease etiology [27,32,33,[49][50][51]. For AD, this can reflect the targeting of each of the two drug binding sites available for AChE, the PAS and the CS, as this produces efficacious cholinesterase inhibition and can confer additional treatment benefits including inhibition of Aβ aggregation and modulation of N-methyl-D-aspartic acid (NMDA) receptors [27,[32][33][34][35].…”

Effect of Water Extract of Mangosteen Pericarp on Donepezil Pharmacokinetics in Mice

“…Numerous delivery systems of donepezil targeting into the brain have been developed, resulting in the improvement of donepezil efficacy as a reversible cholinesterase inhibitor used for the treatment of AD [54][55][56][57]. In addition, tissue distribution can provide information necessary to explain the mechanism of action considering the pharmacological target organ, and the increased concentration of a drug in the brain by co-treated compounds have been suggested as a potential therapy for the treatment of AD [35,58,59].…”

A Preliminary Assessment of the Nutraceutical Potential of Acai Berry (Euterpe sp.) as a Potential Natural Treatment for Alzheimer’s Disease

“…However, ChEI treatment can induce adverse reactions and only addresses one component of the AD disease pathology (insufficient ACh levels), whereas multiple elements of cellular dysfunction may contribute to the disease, including oxidative stress [ 25 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 57 ]. Hence, there is an unmet need to tackle disease aetiology, for example, through a multipronged treatment strategy [ 57 , 58 ]. Indeed, animal models of AD have demonstrated improvements in cognitive function and behavioural defects after antioxidant therapy [ 59 , 60 ].…”