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)

Tacrine (1,2,3,4-tetrahydro-9-acridinamine monohydrate) is an inhibitor of acetylcholinesterase currently used in the treatment of the symptoms of Alzheimer's disease. The present study demonstrates preferential binding of this drug to acidic phospholipids, as revealed by fluorescence polarization, penetration into lipid monolayers, and effects on the thermal phase behavior of dimyristoyl phosphatidic acid (DMPA). A fivefold enhancement in the polarization of tacrine emission is evident above the main phase transition temperature (T(m)) of DMPA vesicles, whereas below T(m) only a 0.75-fold increase is observed. In contrast, the binding of tacrine to another acidic phospholipid, dimyristoylphosphatidylglycerol, did not exhibit strong dependence on T(m). In accordance with the electrostatic nature of the membrane association of tacrine, the extent of binding was augmented with increasing contents of egg PG in phosphatidylcholine liposomes. Furthermore, [NaCl] > 50 mM dissociates tacrine (albeit incompletely) from the liposomes composed of acidic phospholipids. Inclusion of the cationic amphiphile sphingosine in egg PG vesicles decreased the membrane association of tacrine until at 1:1 sphingosine: egg PG stoichiometry binding was no longer evident. Tacrine also penetrated into egg PG but not into egg PC monolayers. Together with broadening of the main transition and causing a shoulder on its high temperature side, the binding of tacrine to DMPA liposomes results in a concentration-dependent reduction both in the combined enthalpy delta H of the above overlapping endotherms and the main transition temperature T(m). Interestingly, these changes in the thermal phase behavior of DMPA as a function of the content of the drug in vesicles were strongly nonlinear. More specifically, upon increasing [tacrine], T(m) exhibited stepwise decrements. Simultaneously, sharp minima in delta H were observed at drug:lipid stoichiometries of approximately 2:100 and 25:100, whereas a sharp maximum in delta H was evident at 18:100. The above results are in keeping with tacrine causing phase separation processes in the bilayer and may also relate to microscopic drug-induced ordering processes within the membrane.
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PMID:Characteristics of the binding of tacrine to acidic phospholipids. 917 42

Tacrine is an acetylcholinesterase inhibitor approved for the treatment of Alzheimer's disease. Unfortunately, reversible hepatotoxicity in about 30% of patients at therapeutic doses limits clinical use. The purpose of this study was to develop and characterize a model of tacrine hepatotoxicity to begin to understand the mechanisms of injury. Rats were given tacrine (10-50 mg/kg, intragatrically) and killed 24 hr later. An increase in serum aspartate aminotransferase was observed up to 35 mg/kg and histology revealed pericentral necrosis and fatty changes. Aspartate aminotransferase was increased from 12 to 24 hr and returned to control values by 32 hr. Livers were perfused in a nonrecirculating system to measure oxygen uptake and trypan blue was infused at the end of each experiment to evaluate tissue perfusion. Time for trypan blue to distribute evenly throughout the liver 3 hr after tacrine treatment was significantly increased (6.9 +/- 1.3 min) compared to controls (1.0 +/- 0.3 min) reflecting decreased tissue perfusion. Tacrine also significantly increased the binding of a hypoxia marker, pimonidazole, in pericentral regions almost 3-fold, and increased portal pressure in vivo significantly. It is hypothesized that tacrine, by inhibiting acetylcholine breakdown in the celiac ganglion, increases sympathetic activity in the liver leading to vascular constriction, hypoxia and liver injury. To test this hypothesis, the hepatic nerve was severed and animals were allowed to recover before tacrine treatment. This procedure significantly reduced serum aspartate aminotransferase, time of dye distribution, pimonidazole binding and portal pressure. Furthermore, a free radical adduct was detected with spin trapping and electron spin resonance spectroscopy 8 hr after tacrine treatment, providing evidence for reoxygenation. When catechin (100 mg/kg, i.p.), a free radical scavenger, was given before tacrine, injury was decreased by about 45%. Furthermore, feeding 5% arginine in the diet significantly reduced portal pressure and time of dye distribution. These data are consistent with the hypothesis that tacrine hepatotoxicity is a hypoxia-reoxygenation injury mediated through the sympathetic nervous system.
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PMID:Development and characterization of a new model of tacrine-induced hepatotoxicity: role of the sympathetic nervous system and hypoxia-reoxygenation. 931 76

Tacrine, a potent acetylcholinesterase inhibitor, has been reported to improve cognitive function in patients with Alzheimer's disease. The present investigation was conducted to elucidate in vivo any interaction between tacrine-induced cortical cholinergic hyperactivity and glutamatergic and GABAergic neurotransmission, which might influence the therapeutic potential of tacrine. Seven days after a daily dosage of 10 mg/kg tacrine i.p. quantitative receptor autoradiography was performed in coronal sections throughout the brain. Repeated administration of tacrine resulted in decreased binding to high-affinity choline uptake, nicotinic and M2-muscarinic acetylcholine receptor sites in a number of cortical regions, while reductions in M1-muscarinic receptor binding were restricted to the cingulate and entorhinal cortex as well as caudate-putamen. Moreover, tacrine injections decreased cortical AMPA receptor binding throughout the brain, while NMDA, kainate, and GABAA receptor binding remained unchanged. Tacrine administration alters cortical AMPA receptor binding in the opposite direction to that observed in patients with Alzheimer's disease, suggesting that tacrine may exert a reversal in up/down-regulation of cortical glutamate receptor subtypes in Alzheimer patients. However, the drug-induced reductions in cortical high-affinity choline uptake sites as well as in nicotinic and in muscarinic acetylcholine receptor binding might partially counteract the cognition-enhancing effects of tacrine produced by acetylcholinesterase inhibition.
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PMID:Repeated administration of tacrine to normal rats: effects on cholinergic, glutamatergic, and GABAergic receptor subtypes in rat brain using receptor autoradiography. 936 55

The senile plaque in Alzheimer's disease (AD) consists mainly of the amyloid beta-peptide (A beta) derived from a larger beta-amyloid precursor protein (betaAPP). The majority of betaAPP is processed by either a secretory or lysosomal/endosomal pathway. Soluble derivatives of betaAPP (sAPP) and A beta generated by the proteolytic processing of full-length betaAPP are normally secreted into the conditioned medium of cultured cells. Tacrine, a centrally active potent cholinesterase inhibitor that has been shown to improve cognitive functions in some patients with AD, inhibits the secretion of sAPP. Here we have investigated whether leupeptin, a lysosomal protease inhibitor, could influence this effect of tacrine. We analyzed levels of betaAPP derivatives in cultured HeLa cells by immunoblotting cell lysates and conditioned media using the monoclonal antibody 22C11. Levels of sAPP normally present in conditioned media were severely reduced by treating cells with tacrine. The treatment of cells with tacrine resulted in a small decrease in the intracellular levels of betaAPP. The effect of treating the cells with tacrine did not depend upon the growing state of the cells as a similar effect was observed when the drug was added either during initial plating of the cells or after the attachment of the cells. The effect of tacrine was not affected by preincubating the cells with low serum in the culture medium. The treatment of cells with tacrine plus leupeptin reduced the secretion of sAPP in the medium to the same degree as did the treatment with tacrine alone, suggesting that the tacrine-mediated inhibition of sAPP release may not involve leupeptin-sensitive proteolytic pathways. The results suggest that the inhibitory effect of tacrine on sAPP secretion is not due to the proteolytic cleavage of the holoprotein in the medium.
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PMID:The effect of tacrine and leupeptin on the secretion of the beta-amyloid precursor protein in HeLa cells. 936 5

We have found earlier that the depolarization-induced release of acetylcholine from the brain could be inhibited by tacrine (tetrahydroaminoacridine) but the mechanism of this action of tacrine was not clarified (S. Tucek, V. Dolezal, J. Neurochem. 56 (1991) 1216). We have now investigated whether tacrine has an effect on the changes in the intracellular concentration of calcium ions ([Ca2+]i) induced by depolarization. Experiments were performed on the cholinergic SN56 neuronal cell line with Fura-2 fluorescence technique of calcium imaging. The depolarization by 71 mmol/l K+ evoked minimum increases of [Ca2+]i up to day 5 in culture. Then the response gradually increased and reached a plateau after 7 days in culture. A similar time course was observed for acetylcholinesterase activity. The effect of K+ ions was concentration-dependent and the concentration of 71 mmol/l K+ evoked maximum [Ca2+]i responses. The increases of [Ca2+]i did not occur in the absence of extracellular calcium. They were mediated by high voltage-activated calcium channels of the L-type and the N-type. Nifedipine (2 micromol/l; L-type calcium channel blocker) and omega-conotoxin GVIA (100 nmol/l; N-type calcium channel blocker) diminished the response to 71 mmol/l K+ by 53% and 39%, respectively, and their effects were additive (decrease to 8% of controls). Non-selective inorganic blocker of voltage-activated calcium channels LaCl3 (0.1 mmol/l) decreased the response by 83%. Tacrine attenuated the [Ca2+]i response in a concentration-dependent manner. At a concentration of 10 micromol/l it inhibited the [Ca2+]i response by 55% and its inhibitory effect was additive with that of omega-conotoxin GVIA but not with that of nifedipine. An equimolar concentration of paraoxon, an irreversible inhibitor of cholinesterases, had no influence on [Ca2+]i response. Tacrine exhibited the same inhibitory effect when paraoxon was present. In conclusion, our data indicate that high-voltage-activated calcium channels of the L-type and the N-type are both present in the SN56 cells but that they are fully expressed only after 6-7 days in culture. Tacrine attenuates the influx of calcium by inhibiting the L-type calcium channels. This inhibitory effect is not a consequence of the anticholinesterase activity of tacrine. The finding that low micromolar concentrations of tacrine may interfere with calcium-dependent events is likely to be of importance for the evaluation of the therapeutic potential of the drug.
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PMID:Effect of tacrine on intracellular calcium in cholinergic SN56 neuronal cells. 937 89

The effect of oral tacrine administration on cortical and hippocampal extracellular acetylcholine (ACh) levels has been investigated by a microdialysis technique, coupled to a HPLC method, in 6- and 22-24-month-old rats. In order to assess whether the increase in extracellular ACh levels was associated with an improvement in the age-related cognitive impairment, the object recognition and step-trough passive avoidance tests were carried out in the treated rats. The extracellular ACh levels measured in the cortex and hippocampus of aged rats without cholinesterase inhibitor in the perfusion Ringer solution were 39 and 54% lower, respectively, than in the young rats. At the dose of 3 mg kg-1, tacrine brought about a three- to four-fold increase in extracellular ACh levels, both in young and aged rats, which peaked 60-80 min after administration and disappeared within the next 60 min. At the same dose, tacrine caused a twofold increase in extracellular ACh levels in the hippocampus of young rats and a sixfold increase in aged rats. The absolute ACh levels at the peak in aged rats were not significantly different from those of young rats. In the object recognition test, aging rats were unable to discriminate between the familiar and novel object. Discrimination was restored by the administration of tacrine at the dose of 1 and 3 mg kg-1, but not 0. 3 mg kg-1 given 30 min before the first trial. Tacrine (3 mg kg-1 p. o.) administered to aging rats before the training trial significantly improved the acquisition of the passive avoidance conditioned response. Our findings demonstrate that tacrine increased both cortical and hippocampal extracellular ACh levels and improved behavioural functions in aged rats.
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PMID:Tacrine administration enhances extracellular acetylcholine in vivo and restores the cognitive impairment in aged rats. 944 13

Tacrine is the first drug having been demonstrated as effective for the treatment of mild and moderate forms of Alzheimer's disease. It works as a potent centrally active inhibitor of acetylcholinesterase and therefore has cholinomimetic properties. The authors evaluate the costs/benefits ratio of this drug taking into account clinical and economical data.
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PMID:[Therapeutic results: tacrine]. 948 Nov 61

Tacrine, an acetyl cholinesterase inhibitor used in the treatment of Alzheimer's disease, often causes reversible abnormalities in liver enzymes, but significant hepatotoxicity is uncommon. We describe fatal hepatic failure associated with tacrine administration. A 75-year-old woman with Alzheimer's disease, taking tacrine for 14 months, developed progressive jaundice. Liver function abnormalities developed during tacrine treatment and led to hepatic failure and death. An extensive evaluation for other etiologies of liver disease was negative. Other potentially hepatotoxic medicines had been administered for at least 2 years before beginning tacrine, and postmortem examination of the liver was consistent with drug-induced hepatotoxicity. Approximately half the patients treated with tacrine have liver enzyme abnormalities develop, primarily in the first 12 weeks of therapy, that resolve with discontinuation of drug or dosage adjustment. Our case of tacrine-associated hepatotoxicity 14 months after the initiation of treatment despite regular biochemical evaluation suggests the potential for delayed and fatal hepatotoxicity with tacrine.
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PMID:Tacrine. A cause of fatal hepatotoxicity? 949 66

Tacrine (tetrahydroaminoacridine) is a reversible cholinesterase inhibitor used for the treatment of Alzheimer's disease. This drug causes an elevation of serum aminotransferases in a limited population of patients. Several in vivo studies failed to elucidate the mechanism for the enzyme elevation but previous in vitro studies have indicated defects in mitochondrial function. In this study, electron microscopic, histochemical, and confocal microscopy techniques were used with primary hepatocyte cultures from humans and rats to examine the sequence of early cellular changes after tacrine exposure. Changes included ribosome alterations as early as 1-2 h following tacrine exposure at concentrations ranging between 0.1 and 1.0 mM. Mitochondrial membrane potential was also altered as indicated by decreased rhodamine 123 uptake with time. Cellular lysosome content increased as indicated by increased staining of fluorescein isothiocyanate (FITC)-conjugated dextran. The results of acid phosphatase histochemistry correlated with the FITC-dextran findings. Additionally, tacrine-related degranulation and vesiculation of the endoplasmic reticulum paralleled the ribosomal and mitochondrial changes. These subcellular changes were reproducible in rat and human hepatocytes, showing for the first time that human hepatocytes can be altered by tacrine. The molecular mechanism of the organelle changes is unknown at this time. Also, the relationship between these subcellular changes in isolated hepatocytes and the transaminase elevation noted in human populations treated with tacrine needs to be clarified.
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PMID:Functional and subcellular organelle changes in isolated rat and human hepatocytes induced by tetrahydroaminoacridine. 952 Jan 38

This work addresses the kinetic analysis of the interaction of tacrine with bovine retina acetylcholinesterase (A ChE, E.C. 3.1.1.7). It was found that the tacrine effect was reversible in nature. Tacrine inhibited bovine retinal AChE activity in a concentration-dependent manner; IC50 was fo to be 8.07 nM. The Michaelis-Menten constant (Ka) for the hydrolysis of acetylthiocholine iodide (ASCh) by AChE was 0.061 mM in the control system, and this value was increased by 54-67% in the tacrine-treated systems. The Vmax was 0.701 mumole/min per milligram protein for the control system, but it was decreased by 26-69% in the tacrine-treated systems. The Lineweaver-Burk plot, Dixon plot, and their secondary replots indicated that the nature of the inhibition was of the partial mixed type, that is, a mixture of competitive and noncompetitive inhibition. The values of Ki and Kt were estimated to be as 4.475 and 8.517 nM, respectively.
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PMID:Sensitivity of bovine retinal acetylcholinesterase (E.C. 3.1.1.7) toward tacrine: kinetic characterization. 958 Aug 77


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