Metformin and Its Sulfenamide Prodrugs Inhibit Human Cholinesterase Activity.

Magdalena Markowicz-Piasecka,Kristiina M. Huttunen,Elżbieta Mikiciuk-Olasik,Łukasz Mateusiak,Joanna Sikora

doi:10.1155/2017/7303096

Magdalena Markowicz-Piasecka, Kristiina M. Huttunen + Show 3 more

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https://doi.org/10.1155/2017/7303096

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Abstract

The results of epidemiological and pathophysiological studies suggest that type 2 diabetes mellitus (T2DM) may predispose to Alzheimer's disease (AD). The two conditions present similar glucose levels, insulin resistance, and biochemical etiologies such as inflammation and oxidative stress. The diabetic state also contributes to increased acetylcholinesterase (AChE) activity, which is one of the factors leading to neurodegeneration in AD. The aim of this study was to assess in vitro the effects of metformin, phenformin, and metformin sulfenamide prodrugs on the activity of human AChE and butyrylcholinesterase (BuChE) and establish the type of inhibition. Metformin inhibited 50% of the AChE activity at micromolar concentrations (2.35 μmol/mL, mixed type of inhibition) and seemed to be selective towards AChE since it presented low anti-BuChE activity. The tested metformin prodrugs inhibited cholinesterases (ChE) at nanomolar range and thus were more active than metformin or phenformin. The cyclohexyl sulfenamide prodrug demonstrated the highest activity towards both AChE (IC50 = 890 nmol/mL, noncompetitive inhibition) and BuChE (IC50 = 28 nmol/mL, mixed type inhibition), while the octyl sulfenamide prodrug did not present anti-AChE activity, but exhibited mixed inhibition towards BuChE (IC50 = 184 nmol/mL). Therefore, these two bulkier prodrugs were concluded to be the most selective compounds for BuChE over AChE. In conclusion, it was demonstrated that biguanides present a novel class of inhibitors for AChE and BuChE and encourages further studies of these compounds for developing both selective and nonselective inhibitors of ChEs in the future.

Highlights

IntroductionType 2 diabetes mellitus (T2DM) is a complex, chronic, and progressive metabolic disease characterized by relative insulin deficiency, insulin resistance (primarily in fat, liver, and muscle cells), and high glucose levels in blood [1, 2]
Type 2 diabetes mellitus (T2DM) is a complex, chronic, and progressive metabolic disease characterized by relative insulin deficiency, insulin resistance, and high glucose levels in blood [1, 2]
In the case of BuChE, it was found that all compounds possess inhibitory properties except for metformin, which presented only weak anti

Summary

Introduction

Type 2 diabetes mellitus (T2DM) is a complex, chronic, and progressive metabolic disease characterized by relative insulin deficiency, insulin resistance (primarily in fat, liver, and muscle cells), and high glucose levels in blood [1, 2]. A review of recent papers and epidemiological data shows an increased risk of developing Alzheimer’s disease (AD), a common neurodegenerative disease characterized by progressive memory shortfall and neuronal loss, in people with T2DM [3,4,5,6]. The pathological characteristics of AD include extracellular amyloid plaques consisting of aggregated amyloid β protein (Aβ), intracellular neurofibrillary tangles (NFTs) comprising hyperphosphorylated tau protein, and neuronal loss [7]. Both acetylcholinesterase (AChE) and decreased acetylcholine (Ach) levels may play a role in the occurrence of AD, as it has been reported that abnormal AChE expression in the AD brain occurs in association with. As García-Ayllón et al have highlighted, the increase in AChE associated with NFTs has not yet been sufficiently explored [10]

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