Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.1.7 (acetylcholinesterase)
 28,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human erythrocytes were treated with different water-soluble amphiphiles (detergents) at sublytic concentrations, whereafter released exovesicles and treated cells were isolated. Lipid analyses showed that exovesicles had a lower cholesterol/phospholipid ratio and a higher phosphatidylserine/phospholipid ratio compared to parent cells. Protein analyses revealed that exovesicles were, relative to their total protein content, depleted in spectrin, actin and band 6 protein and enriched in band 3 protein and acetylcholinesterase. Exovesicles contained all major glycoproteins. By using a radiolabeled amphiphile ([14C]cetyltrimethylammonium bromide) it was shown that the amphiphile/phospholipid ratio was similar in the vesicle membrane and in the parent cell membrane. This indicates that no significant segregation of the intercalated amphiphile between the exovesicle membrane and the parent cell membrane occurs during the vesiculation process. It is suggested that the redistributions of membrane lipids and proteins during the vesiculation process are secondary to the detachment of the cytoskeletal network from the membrane.
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PMID:Lipid and protein composition of exovesicles released from human erythrocytes following treatment with amphiphiles. 814 43

Effects of a peripherally active carbamate (pyridostigmine bromide) and a centrally active organophosphate (OP) nerve agent (soman) on performance by rhesus monkeys of a compensatory tracking (primate equilibrium platform, or PEP) task were measured using a balanced Latin-square design to determine the ED50 for pyridostigmine (0.66 mg/kg) and the up-and-down (titration) method to determine the ED50 for soman (2.50 micrograms/kg). We concluded that the PEP performance model is a sensitive and reliable indicator of anticholinesterase (anti-ChE) behavioral toxicity. We also found that soman, an irreversible inhibitor of acetylcholinesterase (AChE), is more than 100 times more behaviorally disruptive than the reversible peripheral inhibitor pyridostigmine, as indicated by the difference in ED50 doses expressed in molar terms. Soman's behavioral toxicity is severe at levels of serum cholinesterase inhibition (70-80%) at which pyridostigmine does not significantly affect performance. As a prophylactic treatment for OP agent poisoning, pyridostigmine has a substantial safety factor, since behavioral toxicity becomes significant only at approximately four times the proposed therapeutic dose.
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PMID:Acute behavioral toxicity of pyridostigmine or soman in primates. 820 84

Seven men participated in a double-blind study of effects of multiple-dose oral pyridostigmine bromide (PB) on physiological responses to 4-h heat stress tests (HST's) in a hot dry environment, 42 degrees C, 20% relative humidity. Subjects underwent 2 7-d series of tests, separated by 72 h, taking 30 mg PB every 8 h in one series, and placebo in the other. Each HST began right after the 0800 dose of PB or placebo. Subjects drank ad libitum during each HST, and performed two 55-min treadmill walks at about 40% VO2max during the last 2 h. Inhibition of red cell cholinesterase at the start of exercise averaged 30.0% in subjects taking PB, and did not differ significantly among HST's with PB. PB increased sweating and evaporative water loss by about 4%, and lowered chest skin temperature during exercise by 0.7 degrees C; but it had no significant effect on rectal temperature, other skin temperatures, O2 uptake, or fluid balance. PB alone had no significant effect on heart rate (HR), but had a significant interaction with day: although PB had essentially no effect on HR in the 1st HST, its effect increased progressively so that HR during exercise in the 4th HST was 8 beats.min-1 lower with PB. Multiple-dose PB had only slight effects on responses to moderate exercise-heat stress beyond those described after single-dose PB, and we found no adverse effects of multiple-dose PB administration.
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PMID:Seven-day pyridostigmine administration and thermoregulation during rest and exercise in dry heat. 824 Jan 94

Heptylphysostigmine is a new and very promising cholinergic drug for the treatment of Alzheimer disease. A method has been developed for its determination in plasma with a detection limit of 50 pg/ml. The drug was extracted in n-hexane by a simple one-step procedure, after buffering with sodium bicarbonate. Samples were analysed on a 25 cm x 4.6 mm I.D. silica column (5 microns particle size) using a mixture of acetonitrile, methanol and ammonium nitrate as mobile phase. Since this molecule is quite unstable in plasma, pyridostigmine bromide was added to samples to limit the decomposition. Physostigmine was employed as internal standard. The molecule was electrochemically detected by oxidizing potential (+0.75 V). The method was applied to the analysis of blood samples taken from one healthy volunteer administered this drug. In the same subject the inhibition rate of acetylcholinesterase in plasma and red cells was also measured.
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PMID:Determination of heptylphysostigmine in plasma by high-performance liquid chromatography with electrochemical detection. 834 Apr 57

Xylazine induced sedation in mice was observed as a kind of inhibition of exploratory activity. The reversible cholinesterase inhibitor cui xing ning (0.25-1.0 m.kg-1), the precursor of acetylcholine, choline bromide (100-300 mg.kg-1), and the M-receptor agonist arecoline (1.0-5.0 mg.kg-1) were shown to significantly antagonize xylazine (5.0 mg.kg-1) induced sedation. While cui xing ning (0.25 mg.kg-1) shifted the dose-response curve of xylazine induced sedation to the right, hemicholinum-3 (3 micrograms icv), which inhibits the synthesis of acetylcholine, shifted the dose-response curve to the left. These results suggest that the xylazine induced sedation may be partly due to a reduced central cholinergic function. Cui xing ning may have some value in the treatment of xylazine overdose and antagonize the anesthesia induced by anesthetics combined with xylazine.
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PMID:[Antagonistic effects of cholinergic drugs on xylazine induced sedation]. 836 75

The interaction of a benzomorphan opiate with the active site of the catalytic subunit of acetylcholinesterase was studied using photoaffinity labeling. UV irradiation of (-)-N-[3H]allylnormetazocine bound to Torpedo acetylcholinesterase resulted in covalent incorporation of 60-70% of the bound ligand. The labeled catalytic subunit was subjected to chemical cleavage with cyanogen bromide and proteolytic degradation with trypsin, chymotrypsin, and staphylococcal V8 protease. The resulting peptide fragments were purified by high performance liquid chromatography and sequenced in the gas phase. The label was not stable under the conditions of the sequencing, but a peptide fragment consisting of Gln74 to Glu82 was reproducibly labeled. These amino acids are located at the rim of a gorge leading to the active site of the enzyme. Molecular modeling studies then demonstrated that these residues can be placed within van der Waals contact of the (-)-N-[3H]allylnormetazocine molecule while it is bound to the active site of the enzyme.
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PMID:Identification of the benzomorphan opiate binding site on the catalytic subunit of acetylcholinesterase. 838 9

Cholinesterase activity is detectable in the Japanese quail embryo, in the yolk and subembryonic liquid, but not in the albumen. Obviously, this enzyme is deposited by the hen into the yolk and from there it is transferred to the subembryonic liquid. In contrast, in the embryo the enzyme is synthesized by itself and the amount increases with the age of the embryo. By using BW284c51 1,5-bis-(4-allyldimethylammoniumphenyl)pentan-3-one bromide and ISO-OMPA tetraisoprophylpyrophosphoramide as inhibitors, it was found that the enzyme in the embryo is predominantly acetylcholinesterase (EC 3.1.1.7), whereas that in the yolk and subembryonic liquid is butyrylcholinesterase (EC 3.1.1.8). Both types are inhibited by dichlorphos. However, the embryonic enzyme activity is restored within 8 hr, whereas that in the subembryonic liquid remained inactive at least for 72 hr after inhibition. Enzyme inhibition leads to retardation of the development, to reduced accumulation of glucose and amino acids in the subembryonic liquid and finally to death of the embryo, suggesting that the developmental retardation is due to the restricted supply of glucose and amino acids. Surprisingly, most of the embryos die when the embryonic enzyme activity has again been restored.
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PMID:Activity of cholinesterases in the Japanese quail embryo. Effects of dichlorphos on the embryonic development. 842 27

3-Carbamyl-N-allylquinuclidinium bromide (CAB) was synthesized and evaluated for its pharmacological effects on cholinergic activity and for protection in vivo against soman toxicity in guinea pigs. This carbamylated derivative of N-allyl-3-quinuclidinol (NAQ), a potent inhibitor of high-affinity choline uptake, demonstrated stereospecific alterations of cholinergic function as well as protection against soman. The R-isomer, but not the S-isomer, of CAB inhibited erythrocyte acetylcholinesterase (AChE) and plasma pseudocholinesterase (pChE) in a concentration-response manner (IC50 = 25 and 29 microM, respectively). The R-isomer of CAB was also a more potent inhibitor of high-affinity choline uptake (IC50 = 4.8 microM) than S-CAB (IC50 = 63 microM). When R-CAB (10 mumol/kg, i.m.) was administered to guinea pigs 30 min prior to soman in conjunction with atropine (16 mg/kg, i.m.) given 1 min post-soman, the compound significantly reduced lethality up to 5 LD50S. This represents enhanced protection when compared to NAQ (up to 100 mumol/kg); the S-isomer of CAB failed to protect against soman intoxication. The results demonstrate that reversible inhibition of AChE with suppression of acetylcholine synthesis into a single compound, CAB, enhances the protection against organophosphates.
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PMID:3-Carbamyl-N-allylquinuclidinium bromide. Effects on cholinergic activity and protection against soman. 843 96

Apart from being a prominent (inhibitory) neurotransmitter that is widely distributed in the central and peripheral nervous system, gamma-aminobutyric acid (GABA) has turned out to exert trophic actions. In this manner GABA may modulate the neuroplastic capacity of neurons and neuron-like cells under various conditions in situ and in vitro. In the superior cervical ganglion (SCG) of adult rat, GABA induces the formation of free postsynaptic-like densities on the dendrites of principal neurons and enables implanted foreign (cholinergic) nerves to establish functional synaptic contacts, even while preexisting connections of the preganglionic axons persist. Apart from postsynaptic effects, GABA inhibits acetylcholine release from preganglionic nerve terminals and changes, at least transiently, the neurochemical markers of cholinergic innervation (acetylcholinesterase and nicotinic receptors). In murine neuroblastoma cells in vitro, GABA induces electron microscopic changes, which are similar in principle to those seen in the SCG. Both neuroplastic effects of GABA, in situ and in vitro, could be mimicked by sodium bromide, a hyperpolarizing agent. In addition, evidence is available that GABA via A- and/or B-receptors may exert direct trophic actions. The regulation of both types of trophic actions (direct, receptor-mediated vs. indirect, bioelectric activity dependent) is discussed.
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PMID:Modulation by GABA of neuroplasticity in the central and peripheral nervous system. 847 68

Organophosphorus pesticides (OPs) produce optico-autonomic peripheral neuropathy in human populations in districts where a large amount of pesticides have been used in agriculture. This report presents an epidemiological study that was performed in Kanagawa Prefecture. An autopsy case of a professional organophosphorus sprayer is reported. In addition, an experiment was performed to investigate a non-cholinergic chronic toxicity due to a certain OP. The epidemiological study revealed that 64 of 7,435 farmers showed vertical smooth pursuit defect of the eyes, impairments of modulation-transfer function (MTF) of the visual system and abnormal contraction dynamics of the pupil reaction to light stimuli, and a high residual level of OP was found in their blood. These abnormalities were reduced by treatment with antidotes such as atropine, prifinium bromide, and pralidoxime methiodide (PAM). The autopsy findings showed severe retinal degeneration with optic neuropathy and an obviously precocious progression of arteriosclerotic change in heart, brain, and retinal vessels. These findings can not be explained by cholinesterase inhibition alone. Experimental evidence showed that OP produced non-cholinergic impairment such as increase of Ca ions in retinal neurons. A generation of free radicals was noted in tissue-cultured retinal neurons. Blood selenium level was reduced by OP. These non-cholinergic actions may also explain the neural damage caused by long-standing low-dosage contact with OPs.
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PMID:[Ophthalmopathy due to environmental toxic substances especially intoxication by organophosphorus pesticides]. 871 73


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