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.

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.

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.

Evaluation of rivastigmine in Alzheimer's disease

2021 ◽  
Vol 11 (1) ◽  
pp. 35-48
Author(s):  
Kevin Nguyen ◽  
Heidi Hoffman ◽  
Binu Chakkamparambil ◽  
George T Grossberg
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Observational Studies ◽  
Cholinesterase Inhibitors ◽  
Randomized Clinical Trials ◽  
Mortality And Morbidity ◽  
Post Marketing ◽  
Dual Inhibition ◽  
The Brain ◽  
Oral Capsule

Dementia is the major cause of mortality and morbidity in older adults, with Alzheimer's disease (AD) being the most common cause. AD has a significant impact on economic and psychosocial status. Cholinesterase inhibitors (ChEIs) are currently the mainstay in the management of AD. Rivastigmine is the only ChEI that inhibits both acetylcholinesterase and butyrylcholinesterase enzymes in the brain. This dual inhibition makes it potentially more effective for AD patients. Its availability as both a transdermal formulation and oral capsule, may improve adherence rates and care giver satisfaction compared with other ChEIs. To date, the data from randomized clinical trials and post marketing observational studies have shown evidence for an impact on cognitive functions in AD with good safety and tolerability.

scholarly journals A New Perspective on the Treatment of Alzheimer’s Disease and Sleep Deprivation-Related Consequences: Can Curcumin Help?

2022 ◽  
Vol 2022 ◽  
pp. 1-23
Author(s):  
Esra Küpeli Akkol ◽  
Hilal Bardakcı ◽  
Çiğdem Yücel ◽  
Gökçe Şeker Karatoprak ◽  
Büşra Karpuz ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Sleep Deprivation ◽  
Sleep Disturbances ◽  
Neurological Diseases ◽  
Clinical Signs ◽  
Scientific Data ◽  
Age Related ◽  
Different Types ◽  
The Brain

Sleep disturbances, as well as sleep-wake rhythm disorders, are characteristic symptoms of Alzheimer’s disease (AD) that may head the other clinical signs of this neurodegenerative disease. Age-related structural and physiological changes in the brain lead to changes in sleep patterns. Conditions such as AD affect the cerebral cortex, basal forebrain, locus coeruleus, and the hypothalamus, thus changing the sleep-wake cycle. Sleep disorders likewise adversely affect the course of the disease. Since the sleep quality is important for the proper functioning of the memory, impaired sleep is associated with problems in the related areas of the brain that play a key role in learning and memory functions. In addition to synthetic drugs, utilization of medicinal plants has become popular in the treatment of neurological diseases. Curcuminoids, which are in a diarylheptanoid structure, are the main components of turmeric. Amongst them, curcumin has multiple applications in treatment regimens of various diseases such as cardiovascular diseases, obesity, cancer, inflammatory diseases, and aging. Besides, curcumin has been reported to be effective in different types of neurodegenerative diseases. Scientific studies exclusively showed that curcumin leads significant improvements in the pathological process of AD. Yet, its low solubility hence low bioavailability is the main therapeutic limitation of curcumin. Although previous studies have focused different types of advanced nanoformulations of curcumin, new approaches are needed to solve the solubility problem. This review summarizes the available scientific data, as reported by the most recent studies describing the utilization of curcumin in the treatment of AD and sleep deprivation-related consequences.

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.

scholarly journals Machine Learning for Diagnosis of Alzheimer’s Disease and Early Stages

2021 ◽  
Vol 1 (3) ◽  
pp. 182-200
Author(s):  
Julio José Prado ◽  
Ignacio Rojas
Keyword(s):  
Machine Learning ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Stage ◽  
Early Stages ◽  
Wide Range ◽  
Different Types ◽  
Selection Algorithms ◽  
Available Information ◽  
The Brain

According to the WHO, approximately 50 million people worldwide have dementia and there are nearly 10 million new cases every year. Alzheimer’s disease is the most common form of dementia and may contribute to 60–70% of cases. It has been proved that early diagnosis is key to promoting early and optimal management. However, the early stage of dementia is often overlooked and patients are typically diagnosed when the disease progresses to a more advanced stage. The objective of this contribution is to predict Alzheimer’s early stages, not only dementia itself. To carry out this objective, different types of SVM and CNN machine learning classifiers will be used, as well as two different feature selection algorithms: PCA and mRMR. The different experiments and their performance are compared when classifying patients from MRI images. The newness of the experiments conducted in this research includes the wide range of stages that we aim to predict, the processing of all the available information simultaneously and the Segmentation routine implemented in SPM12 for preprocessing. We will make use of multiple slices and consider different parts of the brain to give a more accurate response. Overall, excellent results have been obtained, reaching a maximum F1 score of 0.9979 from the SVM and PCA classifier.

Longitudinal Changes in Individual BrainAGE in Healthy Aging, Mild Cognitive Impairment, and Alzheimer’s Disease

GeroPsych ◽  
2012 ◽  
Vol 25 (4) ◽  
pp. 235-245 ◽  
Author(s):  
Katja Franke ◽  
Christian Gaser
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Healthy Aging ◽  
Brain Aging ◽  
Elderly Subjects ◽  
Additional Increase ◽  
Longitudinal Changes ◽  
Novel Method ◽  
The Brain

We recently proposed a novel method that aggregates the multidimensional aging pattern across the brain to a single value. This method proved to provide stable and reliable estimates of brain aging – even across different scanners. While investigating longitudinal changes in BrainAGE in about 400 elderly subjects, we discovered that patients with Alzheimer’s disease and subjects who had converted to AD within 3 years showed accelerated brain atrophy by +6 years at baseline. An additional increase in BrainAGE accumulated to a score of about +9 years during follow-up. Accelerated brain aging was related to prospective cognitive decline and disease severity. In conclusion, the BrainAGE framework indicates discrepancies in brain aging and could thus serve as an indicator for cognitive functioning in the future.

The Weak Combined Magnetic Fields Reduce the Brain β-Amyloid in an Animal Model of Sporadic Alzheimer's Disease

PIERS Online ◽  
2009 ◽  
Vol 5 (4) ◽  
pp. 311-315 ◽  
Author(s):  
Natalia V. Bobkova ◽  
Vadim V. Novikov ◽  
Natalia I. Medvinskaya ◽  
Irina Yu. Aleksandrova ◽  
Eugenii E. Fesenko
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Animal Model ◽  
Magnetic Fields ◽  
Sporadic Alzheimer’S Disease ◽  
Combined Magnetic Fields ◽  
The Brain

SPECIFIC PROPERTIES OF TUBULIN IN THE PREFRONTAL CORTEX IN CONTROL, SCHIZOPHRENIA AND VASCULAR DEMENTIA

2020 ◽  
pp. 65-71
Author(s):  
Burbaeva G.Sh. ◽  
Androsova L.V. ◽  
Vorobyeva E.A. ◽  
Savushkina O.K.
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Prefrontal Cortex ◽  
Vascular Dementia ◽  
Binding Activity ◽  
Nephelometric Method ◽  
Rate Of Polymerization ◽  
Mental Diseases ◽  
And Control ◽  
The Brain

The aim of the study was to evaluate the rate of polymerization of tubulin into microtubules and determine the level of colchicine binding (colchicine-binding activity of tubulin) in the prefrontal cortex in schizophrenia, vascular dementia (VD) and control. Colchicine-binding activity of tubulin was determined by Sherlinе in tubulin-enriched extracts of proteins from the samples. Measurement of light scattering during the polymerization of the tubulin was carried out using the nephelometric method at a wavelength of 450-550 nm. There was a significant decrease in colchicine-binding activity and the rate of tubulin polymerization in the prefrontal cortex in both diseases, and in VD to a greater extent than in schizophrenia. The obtained results suggest that not only in Alzheimer's disease, but also in other mental diseases such as schizophrenia and VD, there is a decrease in the level of tubulin in the prefrontal cortex of the brain, although to a lesser extent than in Alzheimer's disease, and consequently the amount of microtubules.

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