Comparative Kinetics of Acetyl- and Butyryl-Cholinesterase Inhibition by Green Tea Catechins|Relevance to the Symptomatic Treatment of Alzheimer's Disease.

Edward J Okello,Joshua Mather

doi:10.3390/nu12041090

Abstract

Alzheimer’s disease (AD) is characterised by the apoptosis of cholinergic neurons and the consequent attenuation of acetylcholine mediated neurotransmission, resulting in neurodegeneration. Acetyl-cholinesterase (AChE) and butyryl-cholinesterase (BuChE) are attractive therapeutic targets in the treatment of AD since inhibition of these enzymes can be used to restore synaptic concentrations of acetylcholine. Whilst inhibitors for these enzymes such as galantamine and rivastigmine have been approved for use, none are able to halt the progression of AD and are responsible for the production of troublesome side-effects. Efficacious cholinesterase inhibitors have been isolated from natural plant-based compounds with many demonstrating additional benefits beyond cholinesterase inhibition, such as antioxidation and anti-inflammation, which are key parts of AD pathology. In this study, five natural flavan-3-ol (catechin) compounds: ((-)-epicatechin (EC), catechin, (-)-epicatechin-3-gallate (ECG),) (-)-epigallocatechin (EGC), (-)-epigallocatechin-3-gallate (EGCG), isolated from green tea, were screened for their cholinesterase inhibitory activity using the Ellman assay. The kinetics of inhibition was determined using reciprocal Lineweaver-Burk plots. EGCG was the only compound found to produce statistically significant, competitive inhibition, of both AChE (p < 0.01) and BuChE (p < 0.01) with IC50 values of 0.0148 µmol/mL and 0.0251 µmol/mL respectively. These results, combined with previously identified antioxidative and anti-inflammatory properties, highlight the potential use of EGCG in the treatment of AD, provided it can be delivered to cholinergic neurons in therapeutic concentrations. Further testing of EGCG in vivo is recommended to fully characterise the pharmacokinetic properties, optimal method of administration and efficacy of this novel plant-based compound.

Highlights

Alzheimer’s disease is the most common form of dementia in the UK accounting for 50–75% of cases [1]
Inhibition of AChE and BuChE is likely to be beneficial as both enzymes have been shown to modulate cholinergic neurotransmission which is key in the pathology of Alzheimer’s disease (AD) [15]
Treatment with natural plant-based compounds such as flavan-3-ols could be used to provide more holistic benefits, targeting age-associated memory impairment or multiple areas of AD pathology. This is in contrast to Gal which produces mainly cholinesterase inhibition with troublesome side-effects [19]

Summary

Introduction

Alzheimer’s disease is the most common form of dementia in the UK accounting for 50–75% of cases [1]. Nutrients 2020, 12, 1090 changes in mood [4] These symptoms progressively worsen with patients beginning to experience delusion and aphasia until eventually suffering from difficulties with breathing, eating and moving, especially without significant assistance from carers [4]. The aetiology and pathophysiology of AD is complex and is characterized by the apoptosis of cholinergic neurons, especially those in the limbic and neocortical regions [5] and the consequent attenuation of acetylcholine mediated neurotransmission This cholinergic neuronal apoptosis is thought to result primarily from the abnormal production and processing of the β-amyloid and tau proteins [6,7,8,9,10]. Genetic susceptibility in the form of polymorphism at the APOE gene locus appears to modulate risk with the ε4 variant conferring greater risk of AD development [12]

Results

Discussion

Conclusion