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

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.