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)

The effect of rivastigmine on memory impairments induced in rats by scopolamine (0.5 mg/kg) was assessed in the Morris water maze and passive avoidance tests and compared with that of tacrine (2.5-17.7 mg/kg). Rivastigmine, (0.5-2.5 mg/kg) inhibited cholinesterase in the cortex and hippocampus by 21-60% and antagonised the deficits in working and reference memory. Tacrine (12.5 and 17.7 mg/kg) produced significantly less inhibition of cholinesterase in the hippocampus but more in the striatum than rivastigmine (0.75 and 1.5 mg/kg) and only antagonised the deficit in reference memory. Rivastigmine (1.5 and 2.5 mg/kg) or tacrine (12.5 mg/kg), injected immediately after completion of the acquisition trial in the passive avoidance test, antagonised the deficit induced by scopolamine (1 mg/kg) in memory retention. The inability of higher doses of the cholinesterase inhibitors to antagonise memory deficits induced by scopolamine may be related to excessive cholinergic stimulation in the central nervous system.
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PMID:Effect of rivastigmine on scopolamine-induced memory impairment in rats. 1059 14

Donepezil hydrochloride (donepezil: E2020: (+/-)-2-[(1-benzylpiperidin-4-yl)methyl]-5,6-dimethoxy-indan-1-one monohydrochloride)) is a centrally acting acetylcholinesterase inhibitor developed for the treatment of Alzheimer's disease. In the present study, its inhibitory effect on the activity of cholinesterase ex vivo was evaluated in the brain, plasma, erythrocytes, heart, small intestine, liver and pectoral muscle of young adult as well as aged rats, in comparison with that of tacrine (9-amino-1,2,3,4-tetrahydroacridine hydrochloride). In aged animals, cholinesterase activity in heart, small intestine and pectoral muscle was lower, whereas that in plasma and liver was higher than in young rats. Both groups showed the highest levels in the brain. Donepezil, at doses of 1.25, 2.5 and 5 mg/kg, p.o., inhibited brain, plasma, erythrocyte, liver and pectoral muscle cholinesterase activity in young rats in a dose-dependent manner but had less effect on cholinesterase activity in heart and small intestine. In aged animals, inhibition of cholinesterase activity in the brain, erythrocytes and pectoral muscle by donepezil was more potent than that in young animals. Tacrine, at doses of 5, 10 and 20 mg/kg, p.o., dose-dependently inhibited cholinesterase activity in all tissues of both young and aged animals, but most potently in heart, small intestine and liver. The inhibition of cholinesterase activity by tacrine in the brain, plasma, erythrocytes, heart and liver was more potent in aged rats than in tissues of young rats. Brain and plasma concentrations of unchanged donepezil and tacrine were measured in the same animals as used for the cholinesterase inhibition study. Brain and plasma concentrations of donepezil and tacrine were higher in aged than in young animals. It is concluded that the inhibitory effects of donepezil and tacrine on cholinesterase activity are greater in aged than in young rats, owing to differences in the tissue concentrations of these compounds between young and aged animals. It is also suggested that the effect of donepezil on cholinesterase activity is more tissue-selective than that of tacrine.
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PMID:Inhibitory effects of donepezil hydrochloride (E2020) on cholinesterase activity in brain and peripheral tissues of young and aged rats. 1061 58

Rivastigmine is a cholinesterase inhibitor (ChEI) with a structural formula different from that of currently available ChEIs. Tacrine and donepezil are classified as short-acting or reversible agents since binding to acetylcholinesterase enzyme (AChE) is hydrolyzed within minutes. Rivastigmine is classified as an intermediate-acting or pseudo-irreversible agent due to its long inhibition on AChE of up to 10 hours. Preclinical biochemical studies indicated that rivastigmine has central nervous system selectivity over peripheral inhibition. It ameliorated memory impairment in rats with forebrain lesions. The drug is rapidly absorbed orally, with a bioavailability of 0.355 and low protein binding (40%). Its elimination half-life is less than 2 hours, and it is converted to an inactive metabolite at the site of action, bypassing hepatic metabolic pathways. Its disposition essentially is unaltered in patients with renal or hepatic impairment. It also has dose-dependent effects on AChE inhibition. In the two large multicenter clinical trials (total 1324 patients) that used a forced-dosage titration scheme, rivastigmine 6-12 mg/day was superior to placebo on three cognitive and functioning scales (p<0.001). Gastrointestinal symptoms are the most frequently reported adverse events. They occurred mostly during the dosage titration phase and decreased during the maintenance phase. Rivastigmine offers clinicians another therapeutic agent to treat Alzheimer's disease.
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PMID:Rivastigmine, a new-generation cholinesterase inhibitor for the treatment of Alzheimer's disease. 1064 71

The effects of three cholinesterase inhibitors (physostigmine, E2020, and Tacrine), all of which are to be cognitive enhancers, on the functional regional cerebral blood flow (rCBF) response were studied in young (5.9+/-1.8 years old) and aged (18.0+/-3.3 years old) monkeys under awake conditions using high-resolution positron emission tomography (PET). Under control condition, vibrotactile stimulation elicited increases in the rCBF response in the contralateral somatosensory cortices of both young and aged monkeys, but the degree of increase in rCBF response was significantly lower in aged (115.8%) than that in young monkeys (139.9%). Regional cerebral metabolic rate of glucose (rCMRglc) response to the stimulation, measured using [18F]-2-fluoro-2-deoxy-Dphysostigmine) were consistent with the data obtained by microdialysis. In contrast, the cognitive enhancers did not alter rCBF response to stimulation in young monkeys. The present results demonstrated that the functional change in rCBF response to the stimulation was induced during the aging process by impairment of the coupling mechanism between the neuronal activation and rCBF response. Furthermore, the observation that cognitive enhancers partly restored the functional rCBF response suggested that the coupling mechanism might be regulated via cholinergic neuronal transmission.
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PMID:Age-related impairment of coupling mechanism between neuronal activation and functional cerebral blood flow response was restored by cholinesterase inhibition: PET study with microdialysis in the awake monkey brain. 1070 May 63

Tacrine, an acetylcholinesterase (AChE) inhibitor that has been used in the treatment of Alzheimer's disease, increases available acetylcholine (Ach) levels in the synaptic cleft thereby enhancing the activity of cholinergic pathways. However, excessive stimulation of nicotinic receptors at the neuromuscular junction results in muscle deterioration. We tested whether reversible AChE inhibitors such as tacrine may induce similar effects. In the present study, tacrine administration (7.5 mg/kg twice daily) to rats produces a 20 and 30-fold increase in the number of degenerating cells in leg and diaphragm muscle, respectively, as compared to control. This myopathy is significantly decreased by co-administration of tacrine with the nitric oxide (NO) synthase inhibitor L-NAME. These results show that tacrine can induce myopathy which may be mediated by increased NO production.
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PMID:Tacrine, a reversible acetylcholinesterase inhibitor, induces myopathy. 1081 86

For the first time, kinetic parameters of the effect of tacrine, an anti-cholinesterase inhibitor of therapeutic potential in Alzheimer's disease has been studied on human retinal acetyl-cholinesterase (AChE). Tacrine inhibited the AChE activity in a concentration dependent manner, the IC(50) being about 45 nM. The Michaelis-Menten constant (K(m)) for the hydrolysis of acetylthiocholine iodide was found to be 0.120 mM and this value was increased by 4-52.8% in the presence of tacrine. V(max) was observed to be 2.23 micromol/h per mg protein for the control system, while it was decreased by 14.73-56.25% in the tacrine treated systems. Dixon as well as Lineweaver-Burk plots and their secondary replots indicated that the nature of the inhibition was of the mixed type, i. e. a combination of competitive and noncompetitive inhibition. The values of K(i) and K(I) were estimated to be as 37.76 and 64.36 nM, respectively.
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PMID:Kinetic analysis of the toxicological effect of tacrine (Cognex) on human retinal acetylcholinesterase activity. 1083 30

The effect of chronic treatment with the cholinesterase inhibitor tacrine on nicotinic receptor subtypes was investigated in human SH-SY5Y neuroblastoma cells and in a fibroblast cell line (M10 cells) stably transfected with alpha4beta2 nicotinic receptors. Tacrine significantly increased the number of nicotinic receptors in SH-SY5Y cells, in a concentration dependent manner (10(-9) to 10(-4) M), when using [3H]epibatidine as labelled ligand. Chronic tacrine treatment of M10 cells significantly increased and decreased the number of alpha4beta2 nicotinic receptors in a concentration dependent manner (10(-9) to 5 x 10(-6) M and 2 x 10(-5) to 10(-4) M, respectively). The tacrine induced increase of nicotinic receptors in SH-SY5Y cells, was not blocked in the presence of the nicotinic antagonists tubocurarine or mecamylamine. A further increase in the number of nicotinic receptors was, however, observed in the presence of mecamylamine. This study demonstrates that the effect of tacrine on the number of nicotinic receptor subtypes is different in human SH-SY5Y neuroblastoma and M10 cells. The up-regulation of different nicotinic receptor subtypes obtained with tacrine might be achieved through interaction via different binding sites on the receptor, i.e. the acetylcholine binding site as well as an allosteric site.
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PMID:Tacrine interacts with different sites on nicotinic receptor subtypes in SH-SY5Y neuroblastoma and M10 cells. 1094 45

The present study determines the energy parameters, such as the Gibb's free energy change (deltaG), enthalpy change (deltaH), heat of activation (deltaH*), entropy change (deltaS), temperature coefficient (Q10) and activation energy (Ea), of human retinal acetylcholinesterase (AChE, EC 3.1.1.7) inhibition by tacrine. The stereo-frequency collisions factor (PZ, the number of sterically and energetically favorable collisions occurring between tacrine and AChE) was also studied in this investigation. Tacrine significantly increased the value of deltaG, deltaH, deltaH*, Q10, Ea and PZ factor, and decreased the value of deltaS for AChE. Since there is no known report on the inhibition of human retinal AChE by tacrine, these results were compared with the reported values for the energy parameters of camel retinal and chicken brain AChE inhibition by an anti-cancer drug, cyclophosphamide. The uniqueness of this approach lies in the development of the 'dual substrate and dual temperature' model, which may open up a new, more efficient avenue for the study of various enzyme catalyzed reactions.
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PMID:Thermodynamic analysis of human retinal acetylcholinesterase inhibition using an anti-Alzheimer's drug, tacrine, through the development of a dual substrate and temperature model. 1094 43

There are now several acetylcholinesterase inhibitors in clinical use for the treatment of Alzheimer's disease, however, no systematic comparative studies of their central and peripheral cholinergic mediated effects in rats appear to have been reported. The present study investigated the dose-response characteristics of donepezil, tacrine, rivastigmine and metrifonate in inducing tremor, lacrimation, salivation and hypothermia and the duration of action of these compounds in Lister hooded rats. Data obtained were compared with the clinical observations on these drugs. Three doses of each compound were given orally to establish a dose-response curve for each behaviour, Tremor and lacrimation were scored, salivation was measured by weighing swabs applied to the mouth area and hypothermia was measured with a rectal probe. ED50 values were calculated for tremor. Using a just sub-maximal tremorigenic dose, the duration of response was examined. All four compounds produced dose-dependent increases in tremor and hypothermia. Only tacrine also produced marked salivation and lacrimation. The order of potency (ED50 value in micromol/kg) was rivastigmine (3.7), donepezil (18.0), tacrine (37.5), metrifonate (470). Tremor following tacrine (150 micromol/kg) and donepezil (20 micromol/kg) was prolonged (> 6 h) with a similar hypothermic response. The duration of these responses following metrifonate (777 micromol/kg) and rivastigmine (12.5 micromol/kg) did not exceed 3 h. Tacrine had poor selectivity for central (tremor) versus peripheral (salivation/lacrimation) effects compared to the other compounds. Donepezil also had a sustained duration of action. The data are consistent with clinical results and indicate that simple in-vivo models may assist in the selection of acetylcholinesterase inhibitors with a suitable response profile for use in the symptomatic treatment of Alzheimer's disease.
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PMID:Comparison of donepezil-, tacrine-, rivastigmine- and metrifonate-induced central and peripheral cholinergically mediated responses in the rat. 1110 8

This study presents a comparison between two inhibitors of acetylcholinesterase, tacrine and E2020 (Donepezil), the 5-HT(3) receptor antagonist ondansetron, and the H(3) receptor antagonist thioperamide, in models of cholinergic function and cognition in male, Lister hooded rats. The cognitive tests used were an operant VI20 task, the delayed match to position task (short-term memory) and the 5-choice serial reaction time task (attention). Scopolamine (SCOP) (0.075mg/kg s.c.) was utilised in both the short-term memory and attention tasks to impair performance. Both tacrine (1-30mg/kg) and E2020 (1-10mg/kg) similarly produced overt cholinomimetic signs of likely central origin (hypothermia, tremor), although tacrine produced more profound peripheral cholinomimetic signs (miosis, secretory signs) than E2020. Tacrine (30mg/kg) and E2020 (10mg/kg) reduced the number of reinforcements gained in the VI20 schedule. Similarly, both drugs attenuated the SCOP-impairment models in the short-term memory and attention tasks (1-3mg/kg). Ondansetron (10ng/kg-1mg/kg) and thioperamide (0.2-10mg/kg) failed to elicit overt cholinomimetic signs or influence the number of food reinforcements gained in the VI20 schedule. Neither ondansetron nor thioperamide attenuated the SCOP-induced impairment in either cognitive task. From the present studies, both E2020 and tacrine showed a similar behavioural profile in the models used, although E2020 was about three times more potent. Furthermore, E2020 but not tacrine appeared to show some discrimination in eliciting central and peripheral cholinomimetic signs. The failure of ondansetron and thioperamide to reverse a SCOP-induced deficit in these models is discussed.
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PMID:Effects of anticholinesterase drugs tacrine and E2020, the 5-HT(3) antagonist ondansetron, and the H(3) antagonist thioperamide, in models of cognition and cholinergic function. 1122 48


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