Amat-Ur-Rasool Hafsa, Ahmed Mehboob, Hasnain Shahida, Carter Wayne G
Royal Derby Hospital Centre, School of Medicine, University of Nottingham, Derby DE22 3DT, UK.
Department of Microbiology and Molecular Genetics, University of the Punjab, Lahore 54590, Pakistan.
Brain Sci. 2021 Feb 2;11(2):184. doi: 10.3390/brainsci11020184.
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 acetylcholinesterase (AChE) 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 AChE. 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.
阿尔茨海默病（AD）是一个日益凸显的社会和医疗保健问题。胆碱酯酶抑制剂（ChEIs）用于AD的症状性治疗，但常引发药物不良反应（ADRs）。在此，评估了多奈哌齐、他克林、黄连素和加兰他敏等ChEIs对人或乙酰胆碱酯酶（AChE）蛋白的抑制效力。还对双药组合在分化神经元内直接抑制人AChE的效力进行了量化。对于两种AChE，ChEI效力顺序为：多奈哌齐>他克林>黄连素>加兰他敏。黄连素与他克林（BerTac）、黄连素与加兰他敏（BerGal）以及他克林与多奈哌齐（TacDon）的双药组合在抑制AChE方面均产生协同效果。多奈哌齐与黄连素（DonBer）以及他克林与加兰他敏（TacGal）引发拮抗反应。多奈哌齐与加兰他敏（DonGal）对人AChE具有协同作用，但对AChE具有拮抗作用。将双药组合应用于神经元细胞后，BerTac、BerGal、DonGal和DonBer均表现出对AChE的协同抑制作用，TacDon具有相加作用，TacGal具有拮抗作用。BerGal产生的协同作用最强，可使总药物剂量降低72%。单独的ChEIs或双药组合对神经元细胞相对无毒，仅在浓度比抑制AChE所需浓度高两到三个数量级时才会降低细胞活力。总之，ChEIs的双药组合可能代表了一种治疗AD患者的新方法，具有降低药物剂量、更具成本效益以及降低ADRs发生可能性的特点。
