Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.1.8 (cholinesterase)
12,691 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In Parkinsonian syndromes behavioural symptoms and dementia can be even more debilitating than motor symptoms and are an important predictor for nursing home placement and mortality. Neuropathologically, dementia seems to be primarily related to cortical changes rather than to subcortical alterations. Concerning neurotransmitter systems, the cholinergic system has been proposed to play a key role in cognitive disturbances. Based on studies with patients with Alzheimer disease, the application of cholinesterase inhibitors is vividly discussed also for dementia associated with parkinsonian syndromes. This review focuses on the specific symptoms of dementia in different parkinsonian syndromes and critically questions the effect of cholinergic treatment on cognitive functions in patients with extrapyramidal syndromes and dementia. There is evidence that medication with some cholinesterase inhibitors can enhance cognition as well as activities of daily living in dementia with Parkinson's disease and seems to reduce behavioural disturbances in both dementia with Parkinson's disease and dementia with Lewy bodies. The effect of treatment with cholinesterase inhibitors in progressive supranuclear palsy and corticobasal degeneration warrants carefully designed studies including a sufficient number of patients and symptom-adopted dementia scales.
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PMID:Treatment of dementia in parkinsonian syndromes with cholinesterase inhibitors. 1738 95

Mild cognitive impairment (MCI) refers to persons who are slightly cognitively impaired for age but do not meet the criteria for dementia. MCI has been related to a pre-dementia stage of Alzheimer's disease (AD). However, other possible diagnoses such as cerebro-vascular disease, frontotemporal dementia or normal aging have been considered. Diagnosis, etiology and conversion to dementia are a source of ambiguity in MCI. The aim was to evaluate the opinion of experts on dementia and of general practitioners concerning MCI. A total of 24 experts from Argentina and Brazil (16 neurologists and 8 psychiatrists) and 30 general practitioners agreed to reply to a questionnaire on MCI (adapted from Dubois inventory, 2003). Of these, 92% of experts considered MCI as an ambiguous entity, not necessarily as a "pre-dementia" stage; 63% confirmed a tendency to worsen over the time and 83% of experts decided to initiate treatment using cholinesterase inhibitors, memantine and vitamin E. The opinion on MCI was that a priori it is not only an Alzheimer disease pre-dementia stage, but most of them consider the treatment against AD. MCI is a heterogeneous entity that should be classified as an open category and making it necessary to standardize definitions and design diagnosis guides to better understand Alzheimer disease pre-dementia stage.
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PMID:[Mild cognitive impairment. Survey of attitudes of specialists and general physicians. mild]. 1740 16

In order to reveal the neuroprotective effects of statins that could be of interest for the prevention and treatment of Alzheimer's disease (AD), we investigated the expression of nicotinic acetylcholine receptors (nAChRs) detected by RT-PCR, the activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) by colorimetric determination, and the levels of the alpha-form of secreted beta-amyloid precursor protein (alphaAPPs) by Western blotting in neuroblastoma (SH-SY5Y) cells exposed to lovastatin, atorvastatin, rosuvastatin and simvastatin, respectively. The results indicated that all statins studied, both lipophilic and hydrophilic, induced high expression of alpha7 nAChR, decreased cholinesterase activities, and increased alphaAPPs, which suggests that statins might play important neuroprotective roles in AD treatment.
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PMID:Effects of statins on alpha7 nicotinic receptor, cholinesterase and alpha-form of secreted amyloid precursor peptide in SH-SY5Y cells. 1741 55

Even if a complete recovery is not an available outcome for Alzheimer disease, it is possibile to improve the clinical symptoms (selfsufficiency, cognitive impairment and behavioral disturbances) with pharmacological and non-pharmacological therapies. The treatment of the patient with dementia is a complex one, that cannot rely only on the use of drugs but needs of a global approach that take into account all the different aspect of the disease. The most used drugs are the cholinesterase inhibitors that have been shown to stabilize or slow down cognitive and functional decline and retard institutionalization, but new treatments are on the way. Extremely important is a strong alliance with the family. Non pharmacological cognitive rehabilitation techniques are also useful in potentiating residual cognitive functions in the patient and in supporting the family and the caregivers.
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PMID:[Current therapeutic approach in patients with Alzheimer disease]. 1758 May 20

One of the main hallmarks of Alzheimer's disease (AD) is the brain deposition of senile plaques made up of toxic amyloid beta-peptide (Abeta), which is derived from a larger protein called the beta-amyloid precursor protein (APP). Both APP processing and cholinesterase activity are affected in the AD brain, but, yet, cholinesterase inhibitors (ChEI) remain the primary Food and Drug Administration approved drugs for AD within the United States. Herein, we evaluated the effects of two clinically relevant drugs on the APP pathway, which is presumably involved in AD pathogenesis. Specifically, we compared the actions of the classical ChEI physostigmine (PHY) and its analog phenserine (PHE) on neuronal cell viability, on IC50 and on levels of different amyloid proteins. Interestingly, these drugs share the same chemical backbone, inhibit acetylcholinesterase with similar potency, but differentially affect APP processing. PHE treatment decreased levels of APP in the human neuroblastoma cells (p=0.009) whereas PHY showed a similar but less-pronounced trend, which did not attain statistical significance. PHE treatment significantly decreased levels of Abeta in human neuroblastoma cells (p=0.02) whereas PHY showed no significant change under the same conditions. The divergent actions of these two structurally related drugs on the amyloid pathway indicate that the mechanisms underpinning the cholinergic and the amyloid-lowering properties for this class of drugs are independent of each other.
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PMID:Differential effects of two hexahydropyrroloindole carbamate-based anticholinesterase drugs on the amyloid beta protein pathway involved in Alzheimer's disease. 1762 35

In a previous study, we found that human neural stem cells (HNSCs) exposed to high concentrations of secreted amyloid-precursor protein (sAPP) in vitro differentiated into mainly astrocytes, suggesting that pathological alterations in APP processing during neurodegenerative conditions such as Alzheimer's disease (AD) may prevent neuronal differentiation of HNSCs. Thus, successful neuroplacement therapy for AD may require regulating APP expression to favorable levels to enhance neuronal differentiation of HNSCs. Phenserine, a recently developed cholinesterase inhibitor (ChEI), has been reported to reduce APP levels in vitro and in vivo. In this study, we found reductions of APP and glial fibrillary acidic protein (GFAP) levels in the hippocampus of APP23 mice after 14 days treatment with (+)-phenserine (25 mg/kg) lacking ChEI activity. No significant change in APP gene expression was detected, suggesting that (+)-phenserine decreases APP levels and reactive astrocytes by posttranscription regulation. HNSCs transplanted into (+)-phenserine-treated APP23 mice followed by an additional 7 days of treatment with (+)-phenserine migrated and differentiated into neurons in the hippocampus and cortex after 6 weeks. Moreover, (+)-phenserine significantly increased neuronal differentiation of implanted HNSCs in hippocampal and cortical regions of APP23 mice and in the CA1 region of control mice. These results indicate that (+)-phenserine reduces APP protein in vivo and increases neuronal differentiation of HNSCs. Combination use of HNSC transplantation and treatment with drugs such as (+)-phenserine that modulate APP levels in the brain may be a useful tool for understanding mechanisms regulating stem cell migration and differentiation during neurodegenerative conditions in AD.
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PMID:Modulation of human neural stem cell differentiation in Alzheimer (APP23) transgenic mice by phenserine. 1764 Aug 80

With the goal of developing Alzheimer's disease therapeutics, we have designed and synthesized new piperidine derivatives having dual action of acetylcholinesterase (AChE) and beta-amyloid peptide (Abeta) aggregation inhibition. For binding with the catalytic site of AChE, an ester with aromatic group was designed, and for the peripheral site, another aromatic group was considered. And for intercalating amyloid-beta oligomerization, long and linear conformation with a lipophilic group was considered. The synthetic methods employed for the structure with dual action depended on alcohols with an aromatic ring and the substituted benzoic acids, which are esterificated in the last step of the synthetic pathway. We screened these new derivatives through inhibition tests of acetylcholinesterase, butyrylcholinesterase (BChE), and Abeta(1-42) peptide aggregation, AChE-induced Abeta(1-42) aggregation. Our results displayed that compound 12 showed the best inhibitory potency and selectivity of AChE, and 29 showed the highest selectivity of BChE inhibition. Compounds 15 and 12 had inhibitory activities against Abeta(1-42) aggregation and AChE-induced Abeta aggregation. In the docking model, we confirmed that 4-chlorobenzene of 12 plays the parallel pi-pi stacking against the indole ring of Trp84 in the bottom gorge of AChE. Because the benzyhydryl moiety of 12 covered the peripheral site of AChE in a funnel-like shape, 12 showed good inhibitory potency against AChE and could inhibit AChE-induced Abeta(1-42) peptide aggregation.
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PMID:Synthesis, in vitro assay, and molecular modeling of new piperidine derivatives having dual inhibitory potency against acetylcholinesterase and Abeta1-42 aggregation for Alzheimer's disease therapeutics. 1768 94

The presence of the K variant of the butyrylcholinesterase gene (BCHE-K) has been associated with the severity of Alzheimer's disease (AD)-related neurofibrillary tangles (NFT) and amyloid beta-protein (Abeta). To examine the impact of BCHE-K on the development of initial NFT- and Abeta pathologies in young individuals below the age of 45 years a total of 124 cases (110 cases with NFT-only pathology, 14 cases with Abeta-only pathology) and 104 matched controls were genotyped for BCHE-K. Homozygosity for BCHE-K was highly overrepresented among NFT-only group (8.2%) compared with controls (1%, P = 0.02) or the Abeta-only group (0%). The prevalence of the K allele, however, was comparable among groups. These findings suggest that homozygosity, but not heterozygosity, for BCHE-K is a potential risk factor for the development of NFT pathology in young individuals implicating BCHE-K in the pathogenesis of early AD.
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PMID:Homozygosity for the K variant of BCHE gene increases the risk for development of neurofibrillary pathology but not amyloid deposits at young ages. 1770 16

Alzheimer's disease is the most common form of dementia in industrialized countries. In the European Union, about 54% of dementia cases are believed to be due to Alzheimer's disease. The condition is an age-related neurodegenerative disorder characterized by multiple cognitive deficiencies, including loss of memory, judgment, and comprehension. These manifestations are accompanied by behavioral and mood disturbances. Although no cure has yet been discovered for Alzheimer's disease, symptomatic therapies are now widely available and offer significant relief to patients and benefits to caregivers in terms of reduced care burden. At the start of the 21st century, health technology assessments recommended three agents for the symptomatic treatment of mild to moderate Alzheimer disease: rivastigmine, donepezil, and galantamine. Rivastigmine (Exelon, Novartis Basel-Switzerland) is a slowly reversible inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), while donepezil (Aricept, Pfizer, New York, USA) and galantamine (Reminyl, Janssen, New Jersey, USA) show no functional inhibition of BuChE, and are considered AChE-selective, rapidly-reversible inhibitors. The efficacy of all three agents has been evaluated in large, double-blind, placebo-controlled clinical trials of up to 6 months' duration. Rivastigmine treatment in mild to moderate Alzheimer's disease improves cognition, activities of daily living, and global function.
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PMID:Rivastigmine in the treatment of Alzheimer's disease: an update. 1804 73

Presenilin-1 (PS1) mutations cause many cases of early-onset inherited Alzheimer's disease, in part, by increasing the production of neurotoxic forms of amyloid beta-peptide (Abeta). However, Abeta-independent effects of mutant PS1 on neuronal Ca(2+) homeostasis and sensitivity to excitatory neurotransmitters have been reported. Here we show that cholinergic modulation of hippocampal synaptic plasticity is impaired in PS1 mutant knockin (PS1KI) mice. Whereas activation of muscarinic receptors enhances LTP at CA1 synapses of normal mice, it impairs LTP in PS1KI mice. Similarly, mutant PS1 impairs the ability of the cholinesterase inhibitor phenserine to enhance LTP. The NMDA current is decreased in CA1 neurons of PS1KI mice and is restored by intracellular Ca(2+)chelation. Similar alterations in acetylcholine and NMDA receptor-mediated components of synaptic plasticity are evident in 3xTgAD mice with PS1, amyloid precursor protein and tau mutations, suggesting that the adverse effects of mutant PS1 on synaptic plasticity can occur in the absence or presence of amyloid and tau pathologies.
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PMID:Presenilin-1 mutation impairs cholinergic modulation of synaptic plasticity and suppresses NMDA currents in hippocampus slices. 1806 71


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