scholarly journals Fighting paralysis and dementia: Acetylcholinesterase inhibitors and reactivators in therapy

2010 ◽  
Vol 32 (4) ◽  
pp. 18-23
Author(s):  
Zoran Radi
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Myasthenia Gravis ◽  
Acetylcholinesterase Inhibitors ◽  
Ache Inhibitors ◽  
Cholinergic Neurotransmission ◽  
Key Enzyme

Inhibition of acetylcholinesterase (AChE; EC 3.1.1.7), one of most efficient known enzymes and a key enzyme of cholinergic neurotransmission, can be therapeutically beneficial, primarily in the treatment of Alzheimer's disease, myasthenia gravis and in ophthalmology. In this article, several therapeutic AChE inhibitors and the mechanism of their interaction with AChE are summarized.

scholarly journals Influence of Acetylcholinesterase Inhibitors Used in Alzheimer’s Disease Treatment on the Activity of Antioxidant Enzymes and the Concentration of Glutathione in THP-1 Macrophages under Fluoride-Induced Oxidative Stress

2018 ◽  
Vol 16 (1) ◽  
pp. 10 ◽  
Author(s):  
Marta Goschorska ◽  
Izabela Gutowska ◽  
Irena Baranowska-Bosiacka ◽  
Katarzyna Piotrowska ◽  
Emilia Metryka ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Reactive Oxygen Species ◽  
Alzheimer's Disease ◽  
Antioxidant Enzymes ◽  
Antioxidant Properties ◽  
Reactive Oxygen ◽  
Acetylcholinesterase Inhibitors ◽  
Oxygen Species ◽  
Ache Inhibitors

It has been reported that donepezil and rivastigmine, the acetylcholinesterase (AchE) inhibitors commonly used in the treatment of Alzheimer’s disease (AD), do not only inhibit AChE but also have antioxidant properties. As oxidative stress is involved in AD pathogenesis, in our study we attempted to examine the influence of donepezil and rivastigmine on the activity of antioxidant enzymes and glutathione concentration in macrophages—an important source of reactive oxygen species and crucial for oxidative stress progression. The macrophages were exposed to sodium fluoride induced oxidative stress. The antioxidant enzymes activity and concentration of glutathione were measured spectrophotometrically. The generation of reactive oxygen species was visualized by confocal microscopy. The results of our study showed that donepezil and rivastigmine had a stimulating effect on catalase activity. However, when exposed to fluoride-induced oxidative stress, the drugs reduced the activity of some antioxidant enzymes (Cat, SOD, GR). These observations suggest that the fluoride-induced oxidative stress may suppress the antioxidant action of AChE inhibitors. Our results may have significance in the clinical practice of treatment of AD and other dementia diseases.

Identification of Human Acetylcholinesterase Inhibitors from the Constituents of EGb761 by Modeling Docking and Molecular Dynamics Simulations

2018 ◽  
Vol 21 (1) ◽  
pp. 41-49 ◽  
Author(s):  
Lihu Zhang ◽  
Dongdong Li ◽  
Fuliang Cao ◽  
Wei Xiao ◽  
Linguo Zhao ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Docking ◽  
Serine Proteases ◽  
Colorimetric Method ◽  
Acetylcholinesterase Inhibitors ◽  
Docking Study ◽  
Molecular Docking Study ◽  
Ache Inhibitors ◽  
Starting Point

Aim and Objective: EGb761, a standardized and well-defined product extract of Ginkgo biloba leaves, has beneficial role in the treatment of multiple diseases, particularly Alzheimer's disease (AD). Identification of natural acetylcholinesterase (AChE) inhibitors from EGb761 would provide a novel therapeutic approach against the Alzheimer's disease. Material and Method: A series of 21 kinds of promising EGb761 compounds were selected, and subsequently evaluated for their potential ability to bind AChE enzyme by molecular docking and a deep analysis of protein surface pocket features. Results: Docking results indicated that these compounds can bind tightly with the active site of human AChE, with favorable distinct interactions around several important residues Asp74, Leu289, Phe295, Ser293, Tyr341, Trp286 and Val294 in the active pocket. Most EGB761 compounds could form the hydrogen bond interactions with the negatively charged Asp74 and Phe295 residues. Among these compounds, diosmetin is the one with the best-predicted docking score while three key hydrogen bonds can be formed between small molecule and corresponding residues of the binding site. Besides, other three compounds luteolin, apigenin, and isorhamnetin have better predicted docking scores towards AChE than other serine proteases, i.e Elastase, Tryptase, Factor XA, exhibiting specificity for AChE inhibition. The RMSD and MM-GBSA results from molecular dymamic simulations indicated that the docking pose of diosmetin-AChE complex displayed highly stable, which can be used for validating the accuracy of molecular docking study. Subsequently, the AChE inhibitory activities of these compounds were evaluated by the Ellman's colorimetric method. Conclusion: The obtained results revealed that all the four compounds exhibited modest AChE inhibitory activity, among which Diosmetin manifested remarkable anti-AChE activity, comparable with the reference compound, Physostigmine. It can be deduced that these EGB761 compounds can be regarded as a promising starting point for developing AChE inhibitors against AD.

scholarly journals In silico Structure-based Identification of Novel Acetylcholinesterase Inhibitors Against Alzheimer’s Disease

2018 ◽  
Vol 17 (1) ◽  
pp. 54-68 ◽  
Author(s):  
Kanzal Iman ◽  
Muhammad Usman Mirza ◽  
Nauman Mazhar ◽  
Michiel Vanmeert ◽  
Imran Irshad ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
In Silico ◽  
Neurodegenerative Disorder ◽  
In Silico Analysis ◽  
Acetylcholinesterase Inhibitors ◽  
Binding Energies ◽  
Therapeutic Interventions ◽  
Ache Inhibitors

Objective and Background: Inhibition of acetylcholinesterase (AChE) has gained much importance since the discovery of the involvement of peripheral anionic site as an allosteric regulator of AChE. Characterized by the formation of β-amyloid plaques, Alzheimer's disease (AD) is currently one of the leading causes of death across the world. Progression in this neurodegenerative disorder causes deficit in the cholinergic activity that leads towards cognitive decline. Therapeutic interventions in AD are largely focused upon AChE inhibitors designed essentially to prevent the loss of cholinergic function. The multifactorial AD pathology calls for Multitarget-directed ligands (MTDLs) to follow up on various components of the disease. Considering this approach, other related AD targets were also selected. Structure-based virtual screening was relied upon for the identification of lead compounds with anti-AD effect. Method: Several chemoinformatics approaches were used in this study, reporting four multi-target inhibitors: MCULE-7149246649-0-1, MCULE-6730554226-0-4, MCULE-1176268617-0-6 and MCULE-8592892575-0-1 with high binding energies that indicate better AChE inhibitory activity. Additional in-silico analysis hypothesized the abundant presence of aromatic interactions to be pivotal for interaction of selected compounds to the acetyl-cholinesterase. Additionally, we presented an alternative approach to determine protein-ligand stability by calculating the Gibbs-free energy change over time. Furthermore, this allows to rank potential hits for further in-vitro testing. Results and Conclusion: With no predicted indication of adverse effects on humans, this study unravels four active multi-target inhibitors against AChE with promising affinities and good ADMET profile for the potential use in AD treatment.

Anti-Acetylcholinesterase Derivatives: A Privileged Structural Framework in Drug Discovery to Treat Alzheimer’s Disease

2019 ◽  
Vol 15 (1) ◽  
pp. 8-21
Author(s):  
Monika Bhardwaj ◽  
Vaishali M. Patil ◽  
Rakhi Dhiman ◽  
Satya P. Gupta ◽  
Neeraj Masand
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Acetylcholinesterase Inhibitors ◽  
Synaptic Cleft ◽  
Ache Inhibitors ◽  
Structural Framework ◽  
Natural Alkaloid ◽  
Synthetic Derivatives

Alzheimer’s disease (AD) is a complex neurological disorder characterised by decrease level of ACh and increased AChE expression. Inhibition of AChE is one of the common strategies to treat AD as it leads to increase Ach level quantitatively at the synaptic cleft. Acetylcholinesterase inhibitors (AChEIs) are used to treat various neurodegenerative disorders, and many are FDA approved for the management and cure of AD. AChEIs produce long term symptomatic effect, that contribute in other pathological mechanisms of the disease (e.g. formation of amyloid–β plaques) and have provided a rationale to the discovery of this class of inhibitors. Currently prescribed AChE inhibitors are Galantamine (natural alkaloid) and Rivastigmine (synthetic alkaloid compound) and have been considered beneficial for the treatment of mild to moderate AD. However, there is a need for the discovery of more effective compounds derived from natural sources as well as form synthetic sources as potential AChEIs. Findings and advances about natural and synthetic derivatives as potential sources of AChEIs will be collectively summarised in this review paper.

scholarly journals Assessment of a Potential Synergistic Effect of Souvenaid® in Mild Alzheimer’s Disease Patients on Treatment with Acetylcholinesterase Inhibitors: An Observational, Non-Interventional Study

2021 ◽  
Vol 80 (4) ◽  
pp. 1377-1382
Author(s):  
Félix Viñuela ◽  
Angeles Barro
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Synergistic Effect ◽  
Acetylcholinesterase Inhibitors ◽  
Efficacy And Safety ◽  
Interventional Study ◽  
Clinical Dementia Rating ◽  
Ache Inhibitors ◽  
Real Clinical Practice

We evaluated the efficacy and safety of Souvenaid (a multinutrient supplement) in patients with mild Alzheimer’s disease (AD) in real clinical practice and assessed a potential synergistic effect of acetylcholinesterase (AChE) inhibitors. Clinical Dementia Rating (CDR) scale was evaluated after six months follow-up. Patients were divided into 4 groups according to the treatment they received: Souvenaid + AChE inhibitors (n = 23); only Souvenaid (n = 8); only AChE inhibitors (n = 7); no treatment (n = 16). The Souvenaid + AChE inhibitors and Souvenaid alone groups were associated with significantly lower increases in CDR per month than the AChE inhibitors or no treatment ones. The efficacy of Souvenaid + AChE inhibitors tended to be higher than Souvenaid alone.

scholarly journals Improving Anti-Neurodegenerative Benefits of Acetylcholinesterase Inhibitors in Alzheimer’s Disease: Are Irreversible Inhibitors the Future?

2020 ◽  
Vol 21 (10) ◽  
pp. 3438 ◽  
Author(s):  
Donald E. Moss
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Acetylcholinesterase Inhibitors ◽  
Ache Inhibitor ◽  
Ache Inhibition ◽  
Short Acting ◽  
Ache Inhibitors ◽  
Acting Mechanism ◽  
Long Acting ◽  
High Level

Decades of research have produced no effective method to prevent, delay the onset, or slow the progression of Alzheimer’s disease (AD). In contrast to these failures, acetylcholinesterase (AChE, EC 3.1.1.7) inhibitors slow the clinical progression of the disease and randomized, placebo-controlled trials in prodromal and mild to moderate AD patients have shown AChE inhibitor anti-neurodegenerative benefits in the cortex, hippocampus, and basal forebrain. CNS neurodegeneration and atrophy are now recognized as biomarkers of AD according to the National Institute on Aging-Alzheimer’s Association (NIA-AA) criteria and recent evidence shows that these markers are among the earliest signs of prodromal AD, before the appearance of amyloid. The current AChE inhibitors (donepezil, rivastigmine, and galantamine) have short-acting mechanisms of action that result in dose-limiting toxicity and inadequate efficacy. Irreversible AChE inhibitors, with a long-acting mechanism of action, are inherently CNS selective and can more than double CNS AChE inhibition possible with short-acting inhibitors. Irreversible AChE inhibitors open the door to high-level CNS AChE inhibition and improved anti-neurodegenerative benefits that may be an important part of future treatments to more effectively prevent, delay the onset, or slow the progression of AD.

scholarly journals AChE Inhibition Study for Alzheimer's Disease Treatment: An In-silico Study

2020 ◽  
pp. 119-125
Author(s):  
Mohd Adnan Kausar
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Free Energy ◽  
Hydrophobic Interactions ◽  
Acetylcholinesterase Inhibitors ◽  
Catalytic Site ◽  
Ache Inhibitors ◽  
In Silico Study ◽  
Polar Interactions ◽  
Free Energy Of Binding

Alzheimer's disease (AD) is the most common form of dementia associated with plaques and tangles in the brain. Several acetylcholinesterase inhibitors have been clinically used to delay or halt the progression of the disease. Solanadine (Snd) and gamma solamargine (Gsm) have been shown to inhibit acetylcholinesterase (AChE). The current study attempts to describe the molecular interactions between human brain AChE and inhibitors Snd and Gsm. The free energy of binding and estimated dissociation constant (Ki) for the 'Snd-AChE Catalytic Anionic site (CAS)-interaction' were determined to be –9.51 kcal/mol and 107.54 nM, respectively and the free energy of binding and estimated Ki for the 'Gsm -AChE CAS-interaction' were determined to be – 8.64 kcal/mol and 463.88 nM, respectively. Hydrophobic interactions, polar interactions, and hydrogen bonding play an important role in the correct positioning of Snd within the 'catalytic site' of AChE to permit docking, while hydrophobic interactions and polar interactions play a significant role in the correct positioning of Gsm within the 'catalytic site' of AChE to permit docking. It is hoped that the information provided in this study will help in the design of AChE-inhibitors as anti-Alzheimer agents.

Spirocyclohexadienones as an Uncommon Scaffold for Acetylcholinesterase Inhibitory Activity

2019 ◽  
Vol 15 (4) ◽  
pp. 373-382 ◽  
Author(s):  
Ralph C. Gomes ◽  
Renata P. Sakata ◽  
Wanda P. Almeida ◽  
Fernando Coelho
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Population Aging ◽  
Acetylcholinesterase Inhibitors ◽  
Acetylcholinesterase Activity ◽  
Docking Study ◽  
Biological Properties ◽  
Ache Inhibitor ◽  
Molecular Docking Study

Background: The most important cause of dementia affecting elderly people is the Alzheimer’s disease (AD). Patients affected by this progressive and neurodegenerative disease have severe memory and cognitive function impairments. Some medicines used for treating this disease in the early stages are based on inhibition of acetylcholinesterase. Population aging should contribute to increase the cases of patients suffering from Alzheimer's disease, thus requiring the development of new therapeutic entities for the treatment of this disease. Methods: The objective of this work is to identify new substances that have spatial structural similarity with donepezil, an efficient commercial drug used for the treatment of Alzheimer's disease, and to evaluate the capacity of inhibition of these new substances against the enzyme acetylcholinesterase. Results: Based on a previous results of our group, we prepared a set of 11 spirocyclohexadienones with different substitutions patterns in three steps and overall yield of up to 59%. These compounds were evaluated in vitro against acetylcholinesterase. We found that eight of them are able to inhibit the acetylcholinesterase activity, with IC50 values ranging from 0.12 to 12.67 µM. Molecular docking study indicated that the spirocyclohexadienone, 9e (IC50 = 0.12 µM), a mixedtype AChE inhibitor, showed a good interaction at active site of the enzyme, including the cationic (CAS) and the peripheral site (PAS). Conclusion: We described the first study aimed at investigating the biological properties of spirocyclohexadienones as acetylcholinesterase inhibitors. Thus, we have identified an inhibitor, which provided valuable insights for further studies aimed at the discovery of more potent acetylcholinesterase inhibitors.

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