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)

Paraoxon (O,O-diethyl O-p-nitrophenyl phosphate) is the neurotoxic metabolite of the insecticide parathion (O,O-diethyl O-p-nitrophenyl phosphorothioate). The effects of organophosphorus compounds on peripheral synapses have been attributed to inhibition of cholinesterase and to direct actions on muscarinic and nicotinic receptors, but less is known about the actions of organophosphorus compounds, including paraoxon, in the central nervous system. We investigated initially the effects of paraoxon on spontaneous transmitter release by recording miniature postsynaptic currents (MPSCs) from cultured rat hippocampal neurons using the whole-cell mode of the patch-clamp technique. Paraoxon (0.3 microM) in the presence of tetrodotoxin (0.3 microM) and atropine (1 microM) caused a significant increase in the frequency of gamma-aminobutyric acid- and glutamate-mediated MPSCs, but did not change the peak amplitudes or decay-time constants of these MPSCs. In contrast, application of nicotinic agonists or antagonists did not change the MPSC frequency. The presynaptic effect of paraoxon shown here was not mediated by actions on muscarinic or nicotinic receptors, or by elevated acetylcholine levels secondary to inhibition of cholinesterase. In addition, agonists were applied to assess the postsynaptic effects of paraoxon on excitatory and inhibitory amino acid receptors. Paraoxon (30 microM-1 mM) blocked the ion channels of glycine, gamma-aminobutyric acidA, N-methyl-D-aspartic acid and nicotinic acetylcholine receptors, but not the ion channels of kalnate- and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptors. The combined effects of paraoxon on spontaneous transmitter release and on the functions of several ligand-gated receptors may constitute mechanisms relevant to the neurotoxicity of paraoxon.
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PMID:Paraoxon: cholinesterase-independent stimulation of transmitter release and selective block of ligand-gated ion channels in cultured hippocampal neurons. 881

The preventative effects of bifemelane (4-(o-benzylphenoxy)-N-methylbutylamine hydrochloride) on atherosclerosis in aged rats fed low-calcium diets were investigated. Male 18-month-old Wistar rats were maintained for 90 days on the following: (A) standard diet (n = 7), (B) low calcium, low magnesium, high aluminium diet (n = 8), (C) standard diet plus oral intubation with 10 mg bifemelane/kg daily (n = 6), (D) low calcium and magnesium, high aluminium diet plus oral intubation with 10 mg bifemelane/kg daily (n = 6). All groups were give these diets and water ad lib for 90 days, after which blood samples were taken from the abdominal aorta and samples of aorta were examined for atherosclerotic changes. The serum concentrations of the following were determined: calcium, magnesium, zinc, aluminium, inorganic phosphorus, cholesterol, glutamate-oxaloacetate transaminase, glutamate-pyruvate transaminase, lactate dehydrogenase, cholinesterase, creatine phosphokinase, blood urea nitrogen and N-terminal parathyroid hormone. The only significant differences between the groups in serum chemistry were reduced concentrations of cholinesterase and magnesium in groups B and D, increased aluminium in group B, and increased N-terminal parathyroid hormone in groups B and D. In groups C and D the atherosclerosis was much improved compared with that in groups A and B. It appears that bifemelane largely prevents atherosclerosis caused by calcium deposition in the arteries of rats fed low-calcium diets, due to its effect in maintaining magnesium and calcium in bones.
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PMID:Effects of bifemelane hydrochloride on atherosclerosis in aged rats fed low-calcium diets. 895 29

The P19 embryonal carcinoma cells differentiate into neurons, astrocytes, and fibroblast-like cells following induction with retinoic acid. The cells mature into functional neurons, as determined by their ability to release neurotransmitters in a Ca(2+)- and depolarization-dependent manner. P19 neurons in culture represent a mixed population in terms of their neurotransmitter phenotype. The cholinergic phenotype of these neurons is modulated by culture density. Cholinergic markers, such as the vesicular acetylcholine transporter, acetyl cholinesterase, and choline acetyltransferase, are expressed in about 85% of the cells in sparse cultures and are largely suppressed at high cell densities. In contrast, glutamate release is enhanced in dense P19 neuronal cultures. The factor mediating the density effect is concentrated exclusively on the cell membrane of P19 neurons and not on the nonneuronal cells, which also differentiate from P19 embryonal carcinoma cells. This membrane-associated component retains its functionality, even after membrane fixation. The downregulation of the cholinergic properties in dense cultures is paralleled by a downregulation of the alpha subunit of the ciliary neurotrophic factor (CNTF) receptor. Thus, it is suggested that the membrane-associated factor, which mediates the density effect, downregulates the cholinergic phenotype by inhibiting the responsiveness of these neurons to CNTF. We further suggest that the P19 cell line can serve as a model system for the study of neurotransmitter phenotype acquisition and plasticity throughout neuronal differentiation.
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PMID:Culture density regulates both the cholinergic phenotype and the expression of the CNTF receptor in P19 neurons. 918 41

Modes of action of anthelmintic drugs are described. Some anthelmintic drugs act rapidly and selectively on neuromuscular transmission of nematodes. Levamisole, pyrantel and morantel are agonists at nicotinic acetylcholine receptors of nematode muscle and cause spastic paralysis. Dichlorvos and haloxon are organophosphorus cholinesterase antagonists. Piperazine is a GABA (gamma-amino-butyric acid) agonist at receptors on nematode muscles and causes flaccid paralysis. The avermectins increase the opening of glutamate-gated chloride (GluCl) channels and produce paralysis of pharyngeal pumping. Praziquantel has a selective effect on the tegument of trematodes and increases permeability of calcium. Other anthelmintics have a biochemical mode of action. The benzimidazole drugs bind selectively to beta-tubulin of nematodes, cestodes and fluke, and inhibit microtubule formation. The salicylanilides: rafoxanide, oxyclozanide, brotianide and closantel and the substituted phenol, nitroxynil, are proton ionophores. Clorsulon is a selective antagonist of fluke phosphoglycerate kinase and mutase. Diethylcarbamazine blocks host, and possibly parasite, enzymes involved in arachidonic acid metabolism, and enhances the innate, nonspecific immune system.
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PMID:Modes of action of anthelmintic drugs. 926 48

Since plasma is generally employed for amino acid analysis, we compared amino acid levels in plasma with those in serum for healthy individuals and examined the influence of separation and storage conditions on the stability of the samples. Then, we determined the amino acid levels of frozen serum samples obtained from sarin poisoned patients. A. Comparison of Amino Acid Levels in Plasma and Those in Serum Blood was collected from 5 healthy individuals. Then, heparinated plasma and serum were separated by centrifugation immediately after blood collection. Serum was also separated by centrifugation after standing whole blood at room temperature for 1 hour. Frozen plasma and serum were store at -40 degrees C for 5 months. All were subjected to analysis in an amino acid analyzer. It was found that the cystine (Cys) and 3-methyl-histidine (3-M-His) levels in serum and plasma were affected when stored in a frozen state, that the aspartate (Asp) level was changed according to the method of collecting serum, and that the taurine (Tau) and ornithine (Orn) levels were affected by standing blood. B. Analysis of Blood Taken from Sarin Poisoned Patients Twelve sarin poisoned patients were selected as subjects, and serum cholinesterase (Ch-E) and serum albumin (Alb) levels were determined. Amino acid analysis was conducted using an amino acid analyzer. Serum samples which had been obtained from the 6 patients and frozen and stored at -40 degrees C from 5 months were used for amino acid analysis. As a result, the serum Ch-E level decreased and the Alb level tended to rise. Since the Ch-E/Alb ratio was reduced in the sarin poisoned patients, it is considered useful for discrimination from liver cirrhosis in which both Ch-E and Alb levels decreased. Amino acid levels in the serum obtained from the sarin poisoned patients were compared with those of healthy individuals, both of which had been stored under the same conditions. There were significant differences in Asp, glutamate (Glu), phenylalanine (Phe), 3-M-His, glutamine (Gln), and Cys levels. The Glu, Phe, and Gln levels were not affected by storage of serum in a frozen state, while the Glu and Phe levels were elevated and the Gln level was reduced. Although Cys exhibited lower values in frozen serum samples, the Cys level was elevated with a rise in the serum Ch-E levels. Therefore, we deduced that Cys metabolism disorders also occur in sarin poisoning. As stated above, the Glu and Phe levels were elevated and the Gln and Cys levels were reduced, suggesting the presence of abnormal amino acid metabolism, in patients with sarin-poisoning.
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PMID:[Blood amino acid levels in sarin poisoning patients]. 928 31

This study examined brain regional neurotransmitter level changes as a function of seizure duration following soman intoxication. Rats, implanted with cortical electrodes and pretreated with HI-6, received a convulsant dose of soman. At selected times after seizure onset the EEG recording electrodes were removed and the animal was killed. Spinal cord cholinesterase (ChE) activity was rapidly and maximally depressed, while brain acetylcholine (ACh) levels showed elevations as early as 3 min after soman treatment and reached significantly high levels at time of seizure onset. Norepinephrine (NE) levels decreased starting 5 min after seizure onset and continued to decline. Levels of dopamine (DA) and of its metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid were elevated as early as 5 min after seizure onset and thereafter. The brain levels of aspartate were markedly decreased at and after 20 min of seizures; levels of glutamate were depressed at 80 min in the cortex. Levels of gamma-aminobutyric acid (GABA) were significantly increased in the cortex starting at 20 min after seizure onset, and in the striatum and hippocampus at 80 min after onset. The levels of glutamine, glycine and taurine were not changed at any time studied. These findings are consistent with the notion that inhibition of ChE and elevation of ACh initiate the seizure process, resulting in secondary changes in DA turnover and release of NE, and later changes in excitatory (aspartate, glutamate) and inhibitory (GABA) amino acid transmitters.
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PMID:Neurochemical mechanisms in soman-induced seizures. 928 39

Methamidophos (O,S-dimethyl phosphoroamidothiolate, Tamaron), an organophosphate (OP) anticholinesterase of limited toxicity, is widely used as an insecticide and acaricide. To provide additional insight into the molecular basis of its action, we have used electrophysiological and biochemical techniques to study the effects of methamidophos on the neuromuscular junction of rat and frog and on the central nervous system of rat. Methamidophos has a relatively weak inhibitory action on cholinesterases in rat diaphragm muscle, brain and hippocampal homogenates, with IC50 values on the order of 20-20 microM. An even weaker anticholinesterase activity was found in frog muscle homogenates, with the IC50 being above 300 microM. As further evidence of anticholinesterase activity, methamidophos (1-100 microM) was able to reverse the blockade by d-tubocurarine (0.5-0.7 microM) of neuromuscular transmission in rat phrenic nerve-hemidiaphragm preparations. Inhibition of cholinesterase activity by methamidophos was long lasting, which is consistent with the formation by the agent of a covalent bond with the enzyme's active serine residue. The action was also slowly reversible, which suggests spontaneous reactivation of the enzyme. electrophysiological studies at the rat neuromuscular junction showed that, due to its anticholinesterase activity, methamidophos increased the amplitude and prolonged the decay phase of nerve-evoked and spontaneous miniature end-plate potentials. In contrast to other OP compounds, e.g., paraoxon (Rocha et al., 1996a), methamidophos did not affect neurotransmitter release, nor did it interact directly with the muscle nicotinic acetylcholine receptor. Moreover, it contrast to paraoxon, methamidophos did not affect the whole-cell currents induced by application of acetylcholine, glutamate or gamma-aminobutyric acid recorded to cultured hippocampal neurons. Based on these data, methamidophos appears to have a selective effect on cholinesterase.
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PMID:Methamidophos: an anticholinesterase without significant effects on postsynaptic receptors or transmitter release. 929 8

We examined a chloride (Cl-)-dependent K+ transport (K(+)-Cl- cotransport) and regulatory volume decrease in dog red blood cells with high K+, low Na+, and high glutathione (GSH) content (HK/HG) due to the presence of an Na(+)-K+ pump. The HK/HG cells were separated according to their density, and the age-marker enzyme activities, such as glucose-6-phosphate dehydrogenase and cholinesterase, were determined. Unexpectedly, we found that young cells were heavier (more dense) and smaller in size compared with the old cells, which were lighter (less dense) and larger. The K(+)-Cl- cotransport was nearly 10-fold higher in the most dense cells, representing a 12% fraction of the total population compared with the lightest cohort. Although K(+)-Cl- cotransport in both the dense and the light cells was activated by N-ethylmaleimide, swelling and depletion of cellular divalent cations and the activation of the transport in the dense cells was greater. Both the dense and light cells regulated their volume when they were isosmotically swollen. Therefore, the lower activity of K(+)-Cl- cotransport might not explain the relative large volume in old HK/HG cells. The concentration of GSH and glutamate was higher in the light cells. Thus the higher the GSH and glutamate concentration, the greater the cell volume and the lower the K(+)-Cl- cotransport.
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PMID:K(+)-Cl- cotransport and volume regulation in the light and the dense fraction of high-K+ dog red blood cells. 932 78

To investigate the spinal cellular structures and molecular mechanisms involved in acetylcholinesterase (AChE) release evoked by both glycine (GLY) and glutamate (GLU)--responses that might play a role in chronic neurotoxicity--we analysed AChE histochemistry and histology upon systemic administration of aspartate (ASP), and conducted in vitro experiments in synaptosomes and slices prepared from mouse spinal ventral horns. Upon superfusion and incubation exposure of these preparations to GLY- and GLU-receptor agonists, we assayed both tissue content and release of AChE, butyrylcholinesterase and lactic dehydrogenase. Histochemical reduction of motor neurone (MN) AChE, calcium dependency, decreases in intracellular AChE and the ratio amongst molecular forms released, suggest that both synaptosomal GLY-evoked AChE release (GLY-EAR) and GLU-receptor-elicited AChE release (GEAR) have release sites located at MN presynaptic terminals. These responses exhibited remarkable postnatal regulation. GEAR seems to be mediated through alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid/kainate receptors after the fourth postnatal week and through both NMDA and non-NMDA receptors at earlier stages. Sustained rises of extracellular AChE might link acute excitotoxic injury with several long-lasting pathways leading to chronic neurotoxicity, since AChE molecular properties include: (1) the ability to block cholinergic mechanisms that protect MN against overactivity; (2) activation of ATP-dependent potassium channels; (3) promotion of neurite and axon outgrowth; and possibly (4) stimulation of brain macrophage migration and activation.
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PMID:In vivo and in vitro studies of glycine- and glutamate-evoked acetylcholinesterase release from spinal motor neurones: implications for amyotrophic lateral sclerosis/motor neurone disease pathogenesis. 941 55

We examined whether sites in the lateral parabrachial nucleus (PBN) where L-glutamate produced increases in arterial pressure were involved in mediation of cholinergic inputs to neurons in the rostral ventrolateral medulla (RVLM). Male Wistar rats were anesthetized, paralyzed and artificially ventilated. Unilateral microinjection of L-glutamate into the lateral PBN produced a pressor response. Microinjection of the muscarinic receptor antagonist scopolamine into the unilateral RVLM inhibited the pressor response to L-glutamate injected ipsilaterally into the lateral PBN, whereas microinjection of the cholinesterase inhibitor physostigmine into the RVLM enhanced it. PBN microinjection of L-glutamate also enhanced the firing rate of RVLM sympathoexcitatory neurons and the enhancement of the firing rate was inhibited by scopolamine iontophoretically applied on neurons. PBN injection of L-glutamate produced a tetrodotoxin (TTX)-sensitive release of ACh in the RVLM. Unilateral microinjection of TTX into the lateral PBN inhibited the pressor response induced by RVLM microinjection of physostigmine. These results provide evidence that neurons in the pressor sites of the lateral PBN are involved in mediation of cholinergic inputs responsible for pressor responses in the RVLM.
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PMID:Evidence for involvement of the lateral parabrachial nucleus in mediation of cholinergic inputs to neurons in the rostral ventrolateral medulla of the rat. 960 37


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