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)

Because there is evidence that central cholinergic mechanisms are depleted in dementia, we studied the effects of central cholinergic augmentation on the memory of 5 patients with Alzheimer disease. Patients received placebo, lecithin, physostigmine, or lecithin plus physostigmine in a double-blind study using titrated doses of the acetylcholinesterase inhibitor physostigmine. Memory was evaluated with alternate forms of the selective reminding procedure. Compared with lecithin alone, the combination of physostigmine and lecithin consistently enhanced memory storage and retrieval; physostigmine without lecithin produced no memory facilitation. The strategy of combining a cholinergic agonist and precursor holds promise, although a larger clinical trial is needed.
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PMID:Effects of physostigmine and lecithin on memory in Alzheimer disease. 53 19

Necropsy brain tissue from normal (control) patients and patients with depression and dementia was examined for activities of various cholinergic components, and these related to the degree of senile plaque formation and extent of intellectual impairment. Choline acetyltransferase and acetylcholinesterase activities decreased significantly as the mean plaque count rose, and in depressed and demented subjects the reduction in choline acetyltransferase activity correlated with the extent of intellectual impairment as measured by a memory information test; muscarinic cholinergic receptor binding activity remained unchanged with increasing senile plaque formation but butyrylcholinesterase activity increased. The results suggest a close relation between changes in the cholinergic system and Alzheimer's dementia, but the precise role of the system in this disease remains to be elucidated.
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PMID:Correlation of cholinergic abnormalities with senile plaques and mental test scores in senile dementia. 71 62

The water-soluble proteins of the cerebral gray matter and some enzyme systems (cholinesterase, acetylcholinesterase, lactate dehydrogenase, malate dehydrogenase, acid phosphatase) were studied in 9 autopsy cases of Alzheimer's presenile or senile dementia, 1 case of Pick's disease and 1 case of cerebral arteriosclerosis. The proteins and enzyme patterns were visualized on polyacrylamide gradient gels after electrophoresis. In all patients studied, the profiles of cerebral gray-matter proteins were normal. In the patients with advanced dementia, the enzyme patterns usually were abnormal. Particularly in Alzheimer's disease, the activity of malate dehydrogenase was markedly increased.
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PMID:Some cerebral proteins and enzyme systems in Alzheimer's presenile and senile dementia. 124 83

Several neurotransmitter markers were investigated in the cerebrospinal fluid (CSF) from patients with Alzheimer's disease (AD) (n = 27), Parkinson's disease (PD) (n = 35) and ALS (n = 26) and from control subjects (n = 34) to compare the possible alterations in the biochemical profiles of these different neurodegenerative diseases. The main proportion of the patients represented an early phase of the illness at the time of the diagnosis. Correlations of the degree of dementia and the stage of the disease with CSF measures were evaluated. The CSF levels of somatostatin like-immunoreactivity (SLI) were significantly reduced in AD patients when compared with those of normals and ALS patients. The CSF concentrations of homovanillic acid (HVA) were significantly decreased for PD patients and the decrease focused on the non-demented patients. A trend of decreasing HVA values towards the most advanced stage of Parkinson's disease assessed by Webster's scale was also displayed. The content of 3-methoxy-4-hydroxyphenylglycol (MHPG) in the CSF was higher for ALS patients than for other groups. The lowest 5-hydroxy-indoleacetic acid (5HIAA) levels were observed in the PD group and the lowest acetylcholinesterase (AChE) activities were found in the PD patients with the most severe disease. Changes in CSF measures were too subtle to be beneficial for diagnostic purposes, but adequate for reflecting the different neurochemical profiles of these three degenerative neurological disorders.
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PMID:Neurochemical markers in the cerebrospinal fluid of patients with Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis and normal controls. 134 20

With prolongation of human age rises also the incidence of senile dementia, inclusive dementia of Alzheimer's type (DAT). At the same time the authors present views in the aetiology of this illness, the role of cholinergic mechanisms of the development dementia and they mention DAT treatment strategy focusing attention on a group of drugs-cholinesterase inhibitors.
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PMID:[Present trends in the development of drugs within the cholinesterase inhibitor group as therapeutic agents for Alzheimer's disease]. 145 Dec 5

Three patients with Alzheimer's disease, a 68-year-old woman with mild dementia and 2 men (aged 64 and 72 years) with moderate dementia were treated orally with the cholinesterase inhibitor tacrine (tetrahydroaminoacridine), 80 mg daily, for several months. The patients were investigated using positron emission tomography (PET) prior to, and after 3 weeks and 3 months of treatment. The PET studies involved a multi-tracer system consisting of [18F]-fluoro-deoxy-glucose (18F-FDG) (tracer for glucose metabolism); 11C-butanol (cerebral blood flow) and (S)(-)- and (R)(+)-[N-11C-methyl]-nicotine (nicotinic receptors; cholinergic neural activity). Tacrine treatment increased the uptake of 11C-nicotine to the brain. Significant reduced difference in uptake between the two enantiomers (S)(-)- and (R)(+)11C-nicotine was observed in the frontal and temporal cortices after tacrine treatment in all three patients. The kinetic analysis indicated increased binding of (S)(-)11C-nicotine in brain compatible with a restoration of nicotinic cholinergic receptors. The most pronounced effect was observed after 3 weeks and 3 months treatment in the patient with mild dementia. An increase in cerebral glucose utilization was found in the 68-year-old patient with mild dementia but also slightly in the 64-year-old man with moderate dementia when treated with tacrine for 3 months. Tacrine administration did not affect cerebral blood flow. The PET data obtained after 3 weeks of tacrine treatment was paralleled by improvement in neuropsychological performance. This study shows in vivo by PET neurochemical effects induced in brain by treatment with tacrine to Alzheimer patients. Intervention with tacrine in the early course of the disease might be necessary for clinical improvement.
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PMID:Tacrine restores cholinergic nicotinic receptors and glucose metabolism in Alzheimer patients as visualized by positron emission tomography. 149 41

This paper examines inhibition of acetylcholinesterase (AchE) and butyrylcholinesterase (BuchE) by tetrahydroaminoacridine (THA), an acridine analog under consideration for palliative treatment of Alzheimer's dementia. THA causes linear mixed inhibition of AchE hydrolysis of acetylthiocholine, a cationic substrate (KI = 3.8 x 10(-9) M), and linear competitive inhibition of AchE hydrolysis of 7-acetoxy-4-methylcoumarin, an uncharged substrate (KI = 6.8 x 10(-9) M), and N-methyl-7-dimethylcarbamoxyquinolinium, a cationic carbamate (KI = 1.5 x 10(-8) M). Propidium association with AchE in the presence of saturating concentrations of THA is characterized by a dissociation constant of 7.7 +/- 0.7 x 10(-6) M, a value within 2-fold of the dissociation constant in the absence of THA. Association of THA with AchE is, therefore, not mutually exclusive with association of propidium at the peripheral anionic site. Moreover, THA causes dissociation of decidium complexes with AchE at concentrations compatible with a dissociation constant of 7.0 +/- 0.4 x 10(-9) M. Similar relationships were observed for THA inhibition of BuchE hydrolysis of butyrylthiocholine (KI = 2.5 x 10(-8) M) and dissociation of decidium complexes with BuchE (KD = 1.9 +/- 0.1 x 10(-8) M). These kinetic and equilibrium data uniformly indicate that THA associates with AchE and BuchE with high affinity and that the subsequent inhibition comes about through ligand association at the active center rather than at a peripheral site. The noncompetitive component of inhibition reflects association of THA with the acyl-enzyme intermediate, with subsequent effects on the rate of deacylation.
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PMID:Interaction of tetrahydroaminoacridine with acetylcholinesterase and butyrylcholinesterase. 153 17

Cholinergic replacement therapy for Alzheimer's disease using existing cholinesterase inhibitors is compromised by short duration, meagre benefits restricted to subgroups of patients, and peripheral toxicity. Heptyl physostigmine is a lipophilic carbamate derivative of physostigmine. In rhesus monkeys, heptyl physostigmine (0.2-0.9 mg/kg i.m.) fully reversed a scopolamine-induced cognitive impairment. Following oral administration in squirrel monkeys, heptyl physostigmine (8 mg/kg) induced long-lasting hypothermia (greater than or equal to 4 h), a centrally-mediated cholinergic effect. Erythrocyte acetylcholinesterase activity was inhibited by 86% at the time of peak hypothermia (180 min). Clinical trials with heptyl physostigmine will enable a more rigorous evaluation of cholinomimetic therapy for dementia.
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PMID:Reversal of cognitive impairment by heptyl physostigmine, a long-lasting cholinesterase inhibitor, in primates. 156 24

The pharmacokinetics of tetrahydroaminoacridine (THA) was studied in patients suffering from Alzheimer's dementia. Single doses of the drug were administered by intravenous (15 mg), oral (50 mg) and rectal routes (25 mg). Pharmacokinetic parameters were related to clinical and biochemical effects in patients who, in a separate study, participated in a clinical trial of oral THA. The bioavailability of THA was low and varied considerably between subjects. Clinical improvement and occurrence of elevated liver enzymes correlated positively with drug bioavailability. Acetyl and butyryl cholinesterase activities in the plasma did not change following THA administration. Rectally administered THA had a higher bioavailability than orally administered THA in three subjects who were given the drug by both routes. These results indicate that a clinical trial of rectal THA would be justified as this administration route may improve resorption and diminish first-pass metabolism of the drug in the liver compared with oral administration.
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PMID:Pharmacokinetics of tetrahydroaminoacridine: relations to clinical and biochemical effects in Alzheimer patients. 162 54

The enzymatic activity of acetylcholinesterase (AchE) in the cerebrospinal fluid (CSF) is considered to be a marker of central cholinergic neuron integrity. Then, we evaluated CSF AchE activity in 90 cases of neurological diseases involving cholinergic system and their related disease, and 28 control cases without central organic lesions or abnormal findings in routine CSF study. AchE activity was evaluated according to Ellman's method using acetylthiocholine iodide as a substrate and tetraisopropyl-pyrophosphoramide, a specific inhibitor of butyrylocholinesterase. CSF AchE of Alzheimer type dementia (AD/SDAT, N = 12: 21.9 +/- 4.7 nmol/ml/min) showed no significant change from those of both control group (22.1 +/- 3.9) and vascular dementia (9: 21.7 +/- 6.7). In extrapyramidal diseases, reduction of the activity was observed in Huntington's chorea (HC, 4: 16.3 +/- 1.4) and progressive supranuclear palsy (PSP, 4: 17.6 +/- 1.7), whereas normal activity was shown in Parkinson's disease (PD, 19: 22.5 +/- 4.6), dentatorubropallidoluysian atrophy (DRPLA, 4: 22.6 +/- 4.2) and striatonigral degeneration (SND, 4: 20.4 +/- 4.3). In olivopontocerebellar atrophy (OPCA, N = 16), we disclosed reduced CSF AchE activity (15.8 +/- 2.4) which had significant correlations with the atrophy of the pontine base (r = 0.6017, p less than 0.02) and cerebellar vermis (r = 0.5450, p less than 0.05) in MRI. AchE activity in cerebellar cortical atrophy (CCA, 5: 20.6 +/- 2.2) remained within the control values. Normal activity was demonstrated in both amyotrophic lateral sclerosis (6: 24.3 +/- 7.3) and spinal muscular atrophy (4: 22.9 +/- 3.9).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[CSF acetylcholinesterase activity in central neurological diseases involving cholinergic systems]. 162 49


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