scholarly journals New Acetylcholinesterase Inhibitors for Alzheimer's Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Mona Mehta ◽  
Abdu Adem ◽  
Marwan Sabbagh
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Therapeutic Target ◽  
Cholinesterase Inhibitors ◽  
Treatment Approach ◽  
Acetylcholinesterase Inhibitors ◽  
Symptomatic Treatment ◽  
Symptomatic Improvement ◽  
Ache Inhibition ◽  
Different Types

Acetylcholinesterase (AChE) remains a highly viable target for the symptomatic improvement in Alzheimer's disease (AD) because cholinergic deficit is a consistent and early finding in AD. The treatment approach of inhibiting peripheral AchE for myasthenia gravis had effectively proven that AchE inhibition was a reachable therapeutic target. Subsequently tacrine, donepezil, rivastigmine, and galantamine were developed and approved for the symptomatic treatment of AD. Since then, multiple cholinesterase inhibitors (ChEI) continue to be developed. These include newer ChEIs, naturally derived ChEIs, hybrids, and synthetic analogues. In this paper, we summarize the different types of ChEIs in development and their respective mechanisms of actions. This pharmacological approach continues to be active with many promising compounds.

Cholinesterase Inhibitors for Alzheimer's Disease: Multitargeting Strategy Based on Anti-Alzheimer's Drugs Repositioning

2019 ◽  
Vol 25 (33) ◽  
pp. 3519-3535 ◽  
Author(s):  
Md. Tanvir Kabir ◽  
Md. Sahab Uddin ◽  
Mst. Marium Begum ◽  
Shanmugam Thangapandiyan ◽  
Md. Sohanur Rahman ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cholinesterase Inhibitors ◽  
Treatment Approach ◽  
Symptomatic Treatment ◽  
Symptomatic Improvement ◽  
Ache Inhibition ◽  
Different Types ◽  
Brain Acetylcholine ◽  
The Brain

: In the brain, acetylcholine (ACh) is regarded as one of the major neurotransmitters. During the advancement of Alzheimer's disease (AD) cholinergic deficits occur and this can lead to extensive cognitive dysfunction and decline. Acetylcholinesterase (AChE) remains a highly feasible target for the symptomatic improvement of AD. Acetylcholinesterase (AChE) remains a highly viable target for the symptomatic improvement in AD because cholinergic deficit is a consistent and early finding in AD. The treatment approach of inhibiting peripheral AChE for myasthenia gravis had effectively proven that AChE inhibition was a reachable therapeutic target. Subsequently tacrine, donepezil, rivastigmine, and galantamine were developed and approved for the symptomatic treatment of AD. Since then, multiple cholinesterase inhibitors (ChEIs) have been continued to be developed. These include newer ChEIs, naturally derived ChEIs, hybrids, and synthetic analogues. In this paper, we summarize the different types of ChEIs which are under development and their respective mechanisms of actions.

2',6'-dihydroxy-4'-methoxy dihydrochalcone improves the cognitive impairment of Alzheimer's disease: a structure-activity relationship study

2021 ◽  
Vol 21 ◽  
Author(s):  
Ana E. Gonçalves ◽  
Ângela Malheiros ◽  
Camila A. Cazarin ◽  
Lara de França ◽  
David L. Palomino-Salcedo ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Learning And Memory ◽  
Acetylcholinesterase Inhibitors ◽  
Inhibitory Avoidance ◽  
Symptomatic Treatment ◽  
Memory Test ◽  
Object Recognition Test ◽  
Docking Simulations ◽  
The Brain

Background: Chalcones and dihydrochalcones present potent inhibition of acetylcholinesterase, which is currently considered the most efficient approach for symptomatic treatment of Alzheimer’s disease. Objective: The present study aimed to explore the potential benefits of 2',6'-dihydroxy-4'-methoxy dihydrochalcone on the cognitive deficits of animals submitted to the streptozotocin-induced Alzheimer's model, as well as to evaluate the possible mechanisms of action. Methods: Learning and memory functions of different groups of animals were submitted to the streptozotocin-induced Alzheimer's model (STZ 2.5 mg/mL, i.c.v.) and subsequently treated with 2',6'-dihydroxy-4'-methoxy dihydrochalcone (DHMDC) administered at doses 5, 15, and 30 mg/kg (p.o.), rivastigmine (0,6 mg/kg, i.p.) and vehicle were evaluated in aversive memory test (inhibitory avoidance test) and spatial memory test (object recognition test). Molecular docking simulations were performed to predict the binding mode of DHMDC at the peripheral site of AChE to analyze noncovalent enzyme-ligand interactions. DFT calculations were carried out to study well-known acetylcholinesterase inhibitors and DHMDC. Results: DHMDC markedly increased the learning and memory of mice. STZ caused a significant decline of spatial and aversive memories in mice, attenuated by DHMDC (15 and 30 mg/kg). Furthermore, STZ conspicuously increased lipid peroxidation and compromised the antioxidant levels in mice brains. DHMDC pretreatment significantly increased GSH activity and other oxidative stress markers and decreased TBARS levels in the brain of STZ administered mice. AChE activity was significantly decreased by DHMDC in the brain of mice. Conclusion: The results together point that DHMDC may be a useful drug in the management of dementia.

scholarly journals Multi-target Natural and Nature-Inspired Compounds against Neurodegeneration: A Focus on Dual Cholinesterase and Phosphodiesterase Inhibitors

2021 ◽  
Vol 11 (11) ◽  
pp. 5044
Author(s):  
Giovanni Ribaudo ◽  
Maurizio Memo ◽  
Alessandra Gianoncelli
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Phosphodiesterase Inhibitors ◽  
Acetylcholinesterase Inhibitors ◽  
Symptomatic Treatment ◽  
Brain Regions ◽  
Complex Nature ◽  
Promising Alternative ◽  
Biochemical Mechanisms ◽  
Underlying Mechanisms

Alzheimer’s disease is a memory-related neurodegenerative condition leading to cognitive impairment. Cholinergic deficit, together with other underlying mechanisms, leads the to onset and progression of the disease. Consequently, acetylcholinesterase inhibitors are used for the symptomatic treatment of dementia, even if limited efficacy is observed. More recently, some specific phosphodiesterase isoforms emerged as promising, alternative targets for developing inhibitors to contrast neurodegeneration. Phosphodiesterase isoforms 4,5 and 9 were found to be expressed in brain regions that are relevant for cognition. Given the complex nature of Alzheimer’s disease and the combination of involved biochemical mechanisms, the development of polypharmacological agents acting on more than one pathway is desirable. This review provides an overview of recent reports focused on natural and Nature-inspired small molecules, or plant extracts, acting as dual cholinesterase and phosphodiesterase inhibitors. In the context of the multi-target directed ligand approach, such molecules would pave the way for the development of novel agents against neurodegeneration. More precisely, according to the literature data, xanthines, other alkaloids, flavonoids, coumarins and polyphenolic acids represent promising scaffolds for future optimization.

scholarly journals A critical review of cholinesterase inhibitors as a treatment modality in Alzheimer's disease

2000 ◽  
Vol 2 (2) ◽  
pp. 111-128 ◽  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cholinesterase Inhibitors ◽  
Acetylcholinesterase Inhibitors ◽  
Synaptic Cleft ◽  
Dose Effect ◽  
Number Needed To Treat ◽  
Serious Adverse Events ◽  
Number Of Patients ◽  
Clinical Measures

Early research into Alzheimer's disease launched the cholinergic hypothesis, based on the correlation between central cholinergic deficiency and clinical measures of cognitive decline. This was epitomized in therapeutic strategies employing a variety of procholinergic agents, of which only the inhibitors of cholinesterase (ChE), the enzyme thai hydrolyzes acetylcholine in the synaptic cleft, have been proven clinically viable. Five such agents are reviewed: tacrine and donepezil, which act at the ionic subsite of acetylcholinesterase (AChE), and rivastigmine, galantamine, and metrifonate, which act at its catalytic esteratic subsite. Despite statistical evidence of efficacy from numerous well-controlled multicenter trials, important clinical utility issues remain outstanding: (i) number-needed-to-treat (NNT) analyses, quantifying the number of patients needing to be treated for one patient to show benefit, find values of 3 to 20; (ii) the pivotal trials themselves were conducted in nonrepreseniative populations, largely comprised of physically healthy outpatients with mildto-moderate Alzheimer's disease and a mean age of 72 years (thereby excluding over 30% of typical Alzheimer patients in State of California-funded clinics), treated for up to 6 months; and (Hi) tolerability is underreported and characterized by a positive correlation between dose, effect and cholinergic side effects - potentially serious adverse events include bradycardia, anorexia, weight loss and myasthenia with respiratory depression. Therapies thus require titration and constant monitoring. Nevertheless, acetylcholinesterase inhibitors (AChEls) constitute the first class of effective agents and are likely to remain so in the continuing absence of viable alternatives.

scholarly journals Emetine and Indirubin- 3- monoxime interaction with human brain acetylcholinesterase: A computational and statistical analysis

2022 ◽  
Vol 67 (4) ◽  
pp. 106-114
Author(s):  
Syed Sayeed Ahmad ◽  
Haroon Khan ◽  
Mohammad Khalid ◽  
Abdulraheem SA Almalki
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Binding Energy ◽  
Human Brain ◽  
Acetylcholinesterase Inhibitors ◽  
Symptomatic Treatment ◽  
Docking Studies ◽  
Coefficient Of Determination ◽  
Intermolecular Energy ◽  
Brain Acetylcholinesterase

Alzheimer's disease is a chronic neurodegenerative ailment and the most familiar type of dementia in the older population with no effective cure to date. It is characterized by a decrease in memory, associated with the mutilation of cholinergic neurotransmission. Presently, acetylcholinesterase inhibitors have emerged as the most endorsed pharmacological medications for the symptomatic treatment of mild to moderate Alzheimer's disease. This study aimed to research the molecular enzymatic inhibition of human brain acetylcholinesterase by a natural compound emetine and I3M. Molecular docking studies were used to identify superior interaction between enzyme acetylcholinesterase and ligands. Furthermore, the docked acetylcholinesterase-emetine complex was validated statistically using an analysis of variance in all tested conformers. In this interaction, H-bond, hydrophobic interaction, pi-pi, and Cation-pi interactions played a vital function in predicting the accurate conformation of the ligand that binds with the active site of acetylcholinesterase. The conformer with the lowest free energy of binding was further analyzed. The binding energy for acetylcholinesterase complex with emetine and I3M was -9.72kcal/mol and -7.09kcal/mol, respectively. In the current study, the prediction was studied to establish a relationship between binding energy and intermolecular energy (coefficient of determination [R2 linear = 0.999), and intermolecular energy and Van der wall forces (R2 linear = 0.994). These results would be useful in gaining structural insight for designing novel lead compounds against acetylcholinesterase for the effective management of Alzheimer's disease.

Potent Acetylcholinesterase Inhibitors: Potential Drugs for Alzheimer’s Disease

2020 ◽  
Vol 20 (8) ◽  
pp. 703-715 ◽  
Author(s):  
Hulya Akıncıoğlu ◽  
İlhami Gülçin
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Free Radical ◽  
Acetylcholinesterase Inhibitors ◽  
Symptomatic Treatment ◽  
Work Related ◽  
Β Amyloid ◽  
Hydrolysis Of ◽  
Neurotransmitter Substance

: Alzheimer’s disease (AD) is one of the cognitive or memory-related impairments occurring with advancing age. Since its exact mechanism is not known, the full therapy has still not been found. Acetylcholinesterase (AChE) has been reported to be a viable therapeutic target for the treatment of AD and other dementias. To this end, acetylcholinesterase inhibitors (AChEIs) are commonly used. AChE is a member of the hydrolase enzyme family. A hydrolase is an enzyme that catalyzes the hydrolysis of a chemical bond. AChE is useful for the development of novel and mechanism-based inhibitors. It has a role in the breakdown of acetylcholine (ACh) neurotransmitters, such as acetylcholinemediated neurotransmission. AChEIs are the most effective approaches to treat AD. AChE hydrolyzes ACh to acetate and choline, as an important neurotransmitter substance. Recently, Gülçin and his group explored new AChEIs. The most suggested mechanism for AD is the deficiency of ACh, which is an important neurotransmitter. In this regard, AChEIs are commonly used for the symptomatic treatment of AD. They act in different ways, such as by inhibiting AChE, protecting cells from free radical toxicity and β-amyloid-induced injury or inhibiting the release of cytokines from microglia and monocytes. This review focuses on the role of AChEIs in AD using commonly available drugs. Also, the aim of this review is to research and discuss the role of AChEIs in AD using commonly available drugs. Therefore, in our review, related topics like AD and AChEIs are highlighted. Also, the latest work related to AChEIs is compiled. In recent research studies, novel natural and synthetic AChEIs, used for AD, are quite noteworthy. These studies can be very promising in detecting potent drugs against AD.

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 Anti-neurodegenerative benefits of acetylcholinesterase inhibitors in Alzheimer’s disease: Nexus of cholinergic and nerve growth factor dysfunction

2021 ◽  
Vol 18 ◽  
Author(s):  
Donald E. Moss ◽  
Ruth G. Perez
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Nerve Growth Factor ◽  
Growth Factor ◽  
Symptomatic Treatment ◽  
Ache Inhibition ◽  
Peripheral Tissues ◽  
Nerve Growth ◽  
Ache Inhibitors ◽  
Therapeutic Benefits

: Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is increasingly viewed as a complex multi-dimensional disease without effective treatments. Recent randomized, placebo-controlled studies have shown volume losses of ~0.7% and ~3.5% per year, respectively, in the basal cholinergic forebrain (CBF) and hippocampus in untreated suspected prodromal AD. One year of donepezil treatment reduced these annualized rates of atrophy to about half of untreated rates. Similar positive although variable results have also been found in volumetric measurements of the cortex and whole brain in patients with mild cognitive impairment as well as more advanced AD stages after treatments with all three currently available acetylcholinesterase (AChE) inhibitors (donepezil, rivastigmine, and galantamine). Here we review the anti-neurodegenerative benefits of AChE inhibitors and the expected parallel disease-accelerating impairments caused by anticholinergics, within a framework of the cholinergic hypothesis of AD and AD-associated loss of nerve growth factor (NGF). Consistent with the “loss of trophic factor hypothesis of AD,” we propose that AChE inhibitors enhance acetylcholine-dependent release and uptake of NGF, thereby sustaining cholinergic neuronal viability and thus lowing AD-associated degeneration of the CBF, to delay dementia progression ultimately. We propose that improved cholinergic therapies for AD started early in asymptomatic persons, especially those with risk factors, will delay the onset, progression, or emergence of dementia. The currently available competitive pseudo-irreversible AChE inhibitors are not CNS-selective and thus induce gastrointestinal toxicity that limits cortical AChE inhibition to ~30% (ranges from 19% to 41%) as measured by in vivo PET studies in patients undergoing therapy. These levels of inhibition are marginal about what is required for effective symptomatic treatment of dementia or slowing AD-associated neurodegeneration. In contrast, because of the inherently slow de novo synthesis of AChE in the CNS (about one-tenth the rate of synthesis in peripheral tissues), irreversible AChE inhibitors produce significantly higher levels of inhibition in the CNS than in peripheral tissues. Such an irreversible inhibitor produces ~68% CNS AChE inhibition in patients undergoing therapy and ~80% inhibition in cortical biopsies of non-human primates. The full therapeutic benefits of AChE inhibitors, whether for symptomatic treatment of dementia or disease-slowing, thus would benefit by producing high levels of CNS inhibition. One way to obtain such higher levels of CNS AChE inhibition would be by using irreversible inhibitors.

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