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:3.1.1.7 (acetylcholinesterase)
28,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Alzheimer's disease (AD) is characterized by profound memory loss sufficient to interfere with social and occupational functioning. It is the most common form of dementia, affecting more than 20 million people worldwide. AD is characterized by an insidious loss of memory, associated functional decline, and behavioral disturbances. Patients may live for more than a decade after they are diagnosed with AD, making it the leading cause of disability in the elderly. The incidence of AD ranges from 1 to 4 percent of the population per year, rising from its lowest level at ages 65 to 70 years to rates that may approach 6 percent for those over the age of 85 years. The first neurotransmitter defect discovered in AD involved acetylcholine (ACh). As cholinergic function is required for short-term memory, the cholinergic deficit in AD was also believed to be responsible for much of the short-term memory deficit. Clinical drug trials in patients with AD have focused on drugs that augment levels of ACh in the brain to compensate for the loss of cholinergic function. These drugs have included ACh precursors, muscarinic agonists, nicotinic agonists, and acetylcholinesterase inhibitors. The most highly developed and successful approaches to date have employed acetylcholinestrase inhibition. Although some Food and Drug Administration-approved drugs are available for the treatment of Alzheimer's disease, the outcomes are often unsatisfactory, and there is a place for alternative medicine, in particular, herbal medicine. This paper reviews the clinical effects of a number of commonly used types of herbal medicines for the treatment of AD.
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PMID:Herbal medicine in the treatment of Alzheimer's disease. 1663 67

Early recognition and treatment initiation are pivotal in managing Alzheimer's disease (AD). Once a diagnosis of AD is made, a treatment plan is developed and should include treatment initiation with cholinesterase inhibitors (ChEIs) to improve cognition, management of comorbid conditions, and treat behavioral symptoms. Caregiver compliance is integral to AD treatment success. The purpose of this report is to present two real case studies of "suspected" AD or related dementia and stress the significance of early and accurate diagnosis in disease management. In case 1, a caregiver reports gradual but progressive loss of memory, and the patient himself complains of memory impairment. Neuroimaging analysis confirms "typical " AD. In case 2, initiation of ChEI therapy is followed by substantial clinical improvement in the face of a complex medical picture, and neuroimaging revealing more neurodegenerative changes than could be accounted for by "pure" AD.
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PMID:Recognition and treatment of Alzheimer's disease: a case-based review. 1663 68

Alzheimer's disease is the most common dementia disorder characterized by multiple pathological changes in the brain leading to a progressive memory loss and other cognitive symptoms producing occupational and social disabilities. Although a great deal of progress has been made in recent years in further understanding the genetic aberrations and patho-physiological processes of Alzheimer's disease there is still no cure of the disease. The transmitter replacement therapy is so far the most explored therapy. Three cholinesterase inhibitors have so far been approved and presently in clinical use in many countries. Although the cholinesterase inhibitors generally appear to produce symptomatic effects with palliative effect on existing cognitive disturbances recent data suggest that they also may have effect on progression of the disease including possible neuroprotective effects. Possible interactions between Abeta and cholinergic neurotransmission may exist. Treatment of cells with Abeta causes decreased cholinergic activity. Pretreatment of PC12 cells with cholinesterase inhibitors such as tacrine and donepezil in clinical relevant concentrations can attenuate Abeta (25-35) toxicity through mechanisms which may be mediated via nicotinic receptors. Estrogen has been shown to protect against Abeta toxicity in different cell lines and also to reduce the formation of Abeta. Its mechanism for the neuroprotective effect is however not fully clarified. A potentiation of the clinical effect of cholinesterase inhibitors in Alzheimer patients has been given together with estrogen. Experimental data suggest that the neuroprotective effect of estrogen as studied in PC12 cells was mediated at least partly via the alpha(7) nicotinic receptor. Treatment with Abeta in nanomolar concentrations for 7 days in PC12 cells significantly decreased the number of nicotinic receptor binding sites and mRNA levels. The effects by Abeta on nicotinic receptors are prevented by nicotine pretreatment. The finding suggests a possible link between Abeta and nicotinic receptor deficits in Alzheimer patients in the early course of the disease.
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PMID:Neuroprotection in Alzheimer's disease - new strategies for treatment. 1678 38

The centipede Scolopendra subspinipes mutilans L. Koch ('Wugong'), the beetle Mylabris phalerata Pallas ('Ban mao') and the earthworm Pheretima aspergillum Chen ('DiLong') have a reputation in traditional Chinese medicine for reducing symptoms of central nervous system decline, including memory loss. A series of extracts of all three organisms was tested for acetylcholinesterase (AChE) inhibition and copper ion binding effects, the latter likely to reduce oxidative damage caused by excess copper. The beetle and centipede chloroform extracts showed the strongest AChE inhibitory effects (30.6% inhibition at 105 microg mL(-1) and 32.3% inhibition at 167 microg mL(-1), respectively) and, in the case of the centipede, this was traced to the unsaturated fatty acids present using bioassay-guided fractionation. Cantharidin from the beetle was shown to have AChE activity (31% inhibition at 1 muM, 0.196 microg mL(-1)), making it a major contributor to the activity of the beetle extract. The earthworm showed no AChE inhibitory activity. Since unsaturated fatty acids have not been previously reported to have AChE inhibitory activity, a series of related compounds was tested to determine structure-activity relationships. It was found that activity existed where there was a chain length of more than 16 C atoms with at least one unsaturated bond in the chain. The carboxylic acid group was also necessary for activity. The fatty acids present in the centipede also showed the ability to bind copper ions when tested using a novel thin layer chromatography method designed to detect copper-binding compounds. The activities reported give some support to the use of the beetle and centipede in traditional Chinese medicine for improving cognitive function.
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PMID:Relevant activities of extracts and constituents of animals used in traditional Chinese medicine for central nervous system effects associated with Alzheimer's disease. 1680 60

To date, the primary treatments for Alzheimer's disease with proven efficacy have been acetylcholinesterase inhibitors that prevent the hydrolysis of acetylcholine (ACh) in the synaptic cleft, thereby prolonging its activity. Although these agents have some benefit in alleviating cognitive impairment, they have limited clinical utility because of insufficient efficacy and marginal tolerability. Within the last decade, there has been much experimental support for the use of therapeutics that directly target nicotinic ACh receptors (nAChRs) to improve cognitive function and slow neurodegenerative disease progression. These findings have spurred considerable research efforts to develop ligands selective for nAChRs, such as ABT-418 (Arneric et al., 1995), SIB-1553 (Bontempi et al., 2001), TC-2403 (Lippiello et al., 1996), and TC-2559 (Bencherif et al., 2000). There is abundant evidence that nAChR modulators have the potential to alleviate cognitive impairment in demented states. In addition to improving cognitive function, a large body of research implicates a role for nAChRs in neuroprotection, suggesting potential for disease modification. An impact of nAChR agonists on disease progression would provide an advantage over currently available treatments for memory loss. The profile of previous nAChR-targeted clinical candidates has not been adequate to warrant further development owing to poor oral bioavailability, side effects, and/or lack of efficacy. Thus, a challenge in nAChR drug design and development has been the reduction of undesirable effects that result from activity at specific nAChRs in the CNS and PNS, including cardiovascular toxicity, emesis, seizures, and hypothermia.
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PMID:Ispronicline: a novel alpha4beta2 nicotinic acetylcholine receptor-selective agonist with cognition-enhancing and neuroprotective properties. 1719 10

Information on changes in the central nervous system (CNS) cholinergic systems following exposure to manganese are considerably less extensive than that associated with other neurotransmitter systems. However, experimental and clinical evidence support the notion that cholinergic activity plays a key role in the pathophysiology of manganese-induced neurotoxicity. Manganese acts as a chemical stressor in cholinergic neurons in a region-specific manner causing breakdown of the cellular homeostatic mechanisms. In fact, a number of cholinergic synaptic mechanisms are putative targets for manganese activity: presynaptic choline uptake, quantal release of acetylcholine into the synaptic cleft, postsynaptic binding of acetylcholine to receptors and its synaptic degradation by acetylcholinesterase. Moreover, manganese significantly influences astrocytic choline transport systems and astrocytic acetylcholine-binding proteins. Thus, manganese exerts its effect on the highly dynamic reciprocal relationship between astrocytes and cholinergic neurons. Cholinergic afferents are crucial in the physiology of locomotion, cognition, emotion and behavioral response, and therefore, it is not surprising that the anatomical selectivity of most manganese-induced cholinergic effects is compatible with the clinical correlates of manganism, which involves impairment of emotional response, decline in higher cortical functions and movement disorder. Manganism, also referred to as Parkinson's-like disorder, is initially manifested by a neuropsychiatric syndrome (locura manganica), the most frequent symptoms and signs of which are compulsive behavior, emotional lability, visual hallucinations and flight of ideas, cognitive decline and memory loss. These signs and symptoms are followed by an extrapyramidal syndrome, which shares numerous clinical and pathophysiological characteristics with idiopathic Parkinson's disease (PD). This natural history of disease could be a clinical reflection of the preferential involvement of the cholinergic systems, initially in the septo-hippocampus and later in the basal ganglia. These observations highlight the importance of studying the role of the CNS cholinergic systems in manganese-mediated neurotoxicity.
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PMID:Modulation of cholinergic systems by manganese. 1792 Jan 28

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

The purpose of the present study was to examine the effect of beta-amyloid (Abeta) oligomers, not the fibrils that make up Abeta plaques, on spatial memory and the cholinergic system in rats. Recently, several researchers have suggested that small assemblies of Abeta, Abeta oligomers, caused memory loss during the early stages of Alzheimer's disease without showing cell death. In the present study, the combination of Abeta oligomers and cerebral ischemia, but not cerebral ischemia alone, significantly impaired spatial memory without apoptosis in the CA1 region of the hippocampus. Donepezil, an acetylcholinesterase inhibitor, ameliorated this memory impairment. Therefore we examined acetylcholine (ACh) release from the dorsal hippocampus. A microdialysis study showed that spontaneous release of ACh was not significantly decreased by the combination of Abeta oligomers and cerebral ischemia; however, high K(+)-evoked ACh release was decreased. These results suggest that a combination of Abeta oligomers and cerebral ischemia induces memory impairment by cholinergic synapse dysfunction without apoptosis. This model may be useful for developing new drugs for the treatment of early-phase Alzheimer's disease.
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PMID:Spatial memory impairment without apoptosis induced by the combination of beta-amyloid oligomers and cerebral ischemia is related to decreased acetylcholine release in rats. 1818 22

Individuals with epilepsy commonly experience memory loss. We investigated the safety and tolerability of galantamine in treatment of memory loss in a pilot study of 28 patients with epilepsy, randomly assigned to galantamine (n=13) or placebo (n=15) and followed for a total of 12 weeks. Participants underwent blinded memory assessment at baseline and 12 weeks (Selective Reminding Test, 7/24 Spatial Recall). One participant in the galantamine group had a suspected recurrence of brain neoplasm and increased seizures; all other participants receiving galantamine showed no increase in seizure activity during the trial. Patients in both groups reported mild, tolerable side effects (headache, appetite suppression), with no difference between groups. No significant differences were observed on the memory measures when both groups were retested at Week 12. Galantamine appears to be safe and tolerable in patients with epilepsy. Further studies with larger samples and comparison with other cholinesterase inhibitors should be considered.
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PMID:The safety and tolerability of galantamine in patients with epilepsy and memory difficulties. 1855 48

Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive memory loss and cognitive impairment. It is the most common type of dementia in the ageing population due to a severe loss of cholinergic neurons in selected brain area. At present, acetylcholinesterase inhibitors (AChEI) are the first group of drugs approved by the FDA to treat mild to moderate Alzheimer's disease. Most of these drugs such as huperzine and galanthamine are originally isolated from plants. In this study, the AChE inhibitory activities from extracts of Chinese medicinal herbs that have traditionally been prescribed to treat insomnia and brain function disorders were examined in a 96-well plate assay based on Ellman's method. Both ethanol and aqueous extracts of 26 traditional Chinese medicinal herbs were tested. Inhibitory effects were expressed as the percentage of inhibition. For the herbal extracts that were shown to exert a significant inhibition, dose-dependent inhibitory assays were also performed. Ethanol and aqueous extracts of six herbs were found to have high AChE inhibitory activities in a dose-dependent manner. The IC(50) of these herbal extracts on inhibition of AChE are at around 5-85 microm/ml. The results of this study indicate that there is a great potential to search for novel usage of these medicinal herbs for the treatment of AD.
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PMID:Anti-acetylcholinesterase activities of traditional Chinese medicine for treating Alzheimer's disease. 1857 42


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