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)

In imaging studies of brain functions using pharmacological probes, identification of the time point at which central effects of intravenously infused drugs become stable is crucial to separate the effects of experimental variables from the concomitant changes in drug effects over time. We evaluated the time courses of the pharmacokinetics and pharmacodynamics, including butyrylcholinesterase inhibition and central neural responses, of physostigmine in healthy young subjects. Ten positron emission tomography (PET) scans that alternated between a rest condition (eyes open, ears unplugged) and a working memory for faces (WM) task were acquired in healthy subjects. Subjects in the drug group received a saline infusion for the first two scans, providing a baseline measure, then received an infusion of physostigmine for all subsequent scans. Subjects in the control group received a placebo infusion of saline for all scans. Physostigmine plasma levels and percent butyrylcholinesterase inhibition increased over time (p < 0. 0001), and both became stable by 40 min. Physostigmine decreased reaction time (RT) (p = 0.0005), and this effect was detected after 20 min of infusion and stable thereafter. Physostigmine also decreased regional cerebral blood flow (rCBF) in right prefrontal cortex during task (p = 0.0002), and this effect was detected after 40 min of infusion and stable thereafter. No change in RT or rCBF was observed in the control group. These results indicate that a 40-min infusion of physostigmine was necessary to obtain stable central effects. More generally, we have demonstrated that experimental effects can vary with time, especially during the initial phases of a drug infusion, indicating that it is critical that these changes are controlled.
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PMID:Time course of pharmacodynamic and pharmacokinetic effects of physostigmine assessed by functional brain imaging in humans. 1089 58

Environmental chemicals may be involved in the etiology of breast cancers. Many studies have addressed the association between cancer in humans and agricultural pesticide exposure. Organophosphorous pesticides have been used extensively to control mosquito plagues. Parathion and malathion are organophosphorous pesticides extensively used to control a wide range of sucking and chewing pests of field crops, fruits, and vegetables. They have many structural similarities with naturally occurring compounds, and their primary target of action in insects is the nervous system; they inhibit the release of the enzyme acetylcholinesterase at the synaptic junction. Eserine, parathion, and malathion are cholinesterase inhibitors responsible for the hydrolysis of body choline esters, including acetylcholine at cholinergic synapses. Atropine, a parasympatholytic alkaloid, is used as an antidote to acetylcholinesterase inhibitors. The aim of this study was to examine whether pesticides were able to induce malignant transformation of the rat mammary gland and to determine whether alterations induced by these substances increase the cholinergic activation influencing such transformation. These results showed that eserine, parathion, and malathion increased cell proliferation of terminal end buds of the 44-day-old mammary gland of rats, followed by formation of 8.6, 14.3, and 24.3% of mammary carcinomas, respectively, after about 28 months. At the same time, acetylcholinesterase activity decreased in the serum of these animals from 9.78 +/- 0.78 U/mL in the control animals to 3.05 +/- 0.06 U/mL; 2.57 +/- 0.15 U/mL; and 3.88 +/- 0.44 U/mL in the eserine-, parathion-, and malathion-treated groups, respectively. However, atropine alone induced a significant (p < 0.05) decrease in the acetylcholinesterase activity from the control value of 9.78 +/- 0.78 to 4.38 +/- 0.10 for atropine alone, to 1.32 +/- 0.06 for atropine in combination with eserine, and 2.39 +/- 0.29 for atropine with malathion, and there was no mammary tumor formation. These results indicate that organophosphorous pesticides induce changes in the epithelium of mammary gland influencing the process of carcinogenesis, and such alterations occur at the level of nervous system by increasing the cholinergic stimulation.
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PMID:A rat mammary tumor model induced by the organophosphorous pesticides parathion and malathion, possibly through acetylcholinesterase inhibition. 1140 58

Transcriptional and immunocytological characterization of thymic epithelial (TE) cell line TE750 shows that these cells, like primary TE cell cultures, transcribe alpha-3, alpha-5 and beta-4 acetylcholine receptor (AcChR) subunit genes while expressing cortical, medullary and epithelial differentiation thymic markers. Incubation of TE750 cells with nicotine decreases cell adherence and growth as measured through direct cytological observation and nucleic acid quantification, respectively. Physostigmine, a traditional cholinesterase inhibitor that also activates nicotinic AcChRs, reproduces the effects of nicotine. Strengthening the hypothesis that cholinergic receptors mediate the effects of physostigmine, acetylcholinesterase (AcChase) activity is not detected in TE750 cells. Also, like thymocytes, TE750 cells express choline acetyltransferase (ChAT), indicating that the natural transmitter AcCh can be produced locally within the thymic parenchyma. Taken together these findings indicate that TE750 cells in culture represent a suitable in vitro system for the analysis of cholinergic mechanisms operational in the thymic epithelium.
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PMID:Thymic epithelial cell line expresses transcripts encoding alpha-3, alpha-5 and beta-4 subunits of acetylcholine receptors, responds to cholinergic agents and expresses choline acetyl transferase. An in vitro system to investigate thymic cholinergic mechanisms. 1143 Oct 5

The widely used organophosphate pesticide chlorpyrifos is a suspected neuroteratogen. In the current study, we compared the effects of chlorpyrifos and its major metabolites in two in vitro models, neuronotypic PC12 cells and gliotypic C6 cells. Chlorpyrifos inhibited DNA synthesis in both cell lines but had a greater effect on gliotypic cells. Chlorpyrifos oxon, the active metabolite that inhibits cholinesterase, also decreased DNA synthesis in PC12 and C6 cells with a preferential effect on the latter. Trichloropyridinol, the major catabolic product of chlorpyrifos, had a much smaller, but nevertheless statistically significant, effect that was equivalent in both cell lines. Diazinon, another organophosphate pesticide, also inhibited DNA synthesis with preference toward C6 cells, but was less effective than was chlorpyrifos. Physostigmine, a non-organophosphate cholinesterase inhibitor, was less effective than either chlorpyrifos or diazinon, but still caused significant inhibition of DNA synthesis in C6 cells. We also found that the addition of sera protected the cells from the adverse effects of chlorpyrifos and that the effect could be reproduced by addition of albumin. These results indicate that chlorpyrifos and other organophosphates such as diazinon have immediate, direct effects on neural cell replication, preferentially for gliotypic cells. In light of the protective effect of serum proteins, the fact that the fetus and newborn possess lower concentrations of these proteins suggests that greater neurotoxic effects may occur at blood levels of chlorpyrifos that are nontoxic to adults.
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PMID:Developmental neurotoxicity of chlorpyrifos modeled in vitro: comparative effects of metabolites and other cholinesterase inhibitors on DNA synthesis in PC12 and C6 cells. 1167 19

Parasympathomimetics or cholinesterase inhibitors taken orally may relieve dry-mouth symptoms, but this route of administration is often associated with adverse systemic reactions. In the present study, an animal model was worked out aimed at stimulating the submucosal glands and avoiding systemic effects. In the anesthetized ferret, saliva from the parotid, sublingual and submandibular glands was prevented from reaching the mouth. Vehicle or physostigmine was applied topically for 10 min on the buccal and labial mucosa on one side, while the other side served as a control. Fluid from each side was collected every 5 min Mean basal secretion was 0.17 mg 5 min(-1). The response to physostigmine 0.1% did not exceed that of the vehicle. At higher concentrations the responses lasted 80-120 min. Peak secretion was nine (0.25% physostigmine), 13 (0.5% physostigmine) and 40 (1% physostigmine) times higher than baseline. At 1% physostigmine, the secretion from the control side was elevated, and a small flow from the duct-cannulated parotid gland occurred, indicating systemic effects. Arterial blood pressure was well maintained. Additional observations on the duct-cannulated zygomatic gland showed that secretion from this gland increased already within the 10-min period of application of physostigmine to the overlying mucosa. The distance between the mucosa and the zygomatic gland was only about 1 mm. Physostigmine-induced secretion was abolished by atropine. Local gland stimulation may be an attractive alternative for the treatment of dry mouth.
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PMID:Secretion from submucosal salivary glands of the ferret in response to a cholinesterase inhibitor applied onto the oral mucosa. 1212 Jul 9

This study is drawn from a work programme aimed at developing improved medical counter measures for nerve agent poisoning. Guinea-pigs were administered pyridostigmine (5.1 microg/h) or physostigmine (4.7 microg/h) and hyoscine (1.94 microg/h) for 6 days via a subcutaneously implanted mini osmotic pump. Pyridostigmine inhibited red cell acetylcholinesterase (AChE) by 44.2 +/- 2.7% and plasma cholinesterase (ChE) by 29.9 +/- 1.8%. Physostigmine and hyoscine inhibited red cell AChE by 18.7 +/- 3.7% and plasma ChE by 44.1 +/- 3.1%. On day 6, animals were challenged with a lethal dose of tabun (GA; 125 microg/kg), sarin (GB; 51.2 microg/kg), soman (GD; 31.2 microg/kg), GF (50 microg/kg) or VX (11.25 microg/kg) administered by the subcutaneous route. Animals were closely observed for signs of poisoning. The time to the onset of signs of poisoning was similar for all the agents except for VX, which showed a delay compared to the other agents. Following pretreatment with either pyridostigmine or physostigmine and hyoscine most animals survived for 2-3 h following nerve agent administration. In contrast, only physostigmine and hyoscine prevented or reduced the duration of the signs of incapacitation and the temperature drop produced by all the agents. Pyridostigmine-pretreated animals showed little or no recovery from incapacitation prior to death. Physostigmine and hyoscine pretreatment provided statistically (P < 0.05) better protection against GB, GD and VX lethality (24 h) than pyridostigmine pretreatment and better protection against GA and GF lethality.
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PMID:Physostigmine and hyoscine improves protection against the lethal and incapacitating effects of nerve agent poisoning in the guinea-pig. 1238 61

Physostigmine is an anti-cholinesterase used for the pretreatment of a poisoning caused by highly toxic organophosphorus neurotoxins. The aim of this study is to design a polymeric microparticle system for sustained release of physostigmine. In this paper, we have attempted to encapsulate physostigmine in microparticles made from poly(D,L-lactide-co-glycolide) (PLGA) with various contents of glycolide and poly(D,L-lactide) (PLA) using spray-drying and single emulsion techniques. It was found that during the single emulsion process, most of the physostigmine molecules were lost in the external aqueous phase. However, more than 90% encapsulation efficiency of physostigmine was obtained using the spray-drying technique. SEM micrographs revealed that spherical microparticles containing physostigmine with a smooth surface were yielded with PLA, PLGA 50:50, RG 502 (PLGA 50:50 with a lower molecular weight) and PLGA 65:35 but PLGA 85:15, PLGA 75:25 and PLGA 50:50 with a high concentration produced microparticles with irregular shapes. An increased inlet temperature yielded a higher physostigmine release rate from the PLA microparticles. Physostigmine release from the microparticles showed a biphasic pattern, characterized by an initial burst release followed by a sustained release for PLGA 65:35, PLGA 50:50 and RG 502 or a non-detectable release for PLGA 85:15, PLGA 75:25 and PLA. A sustained-release of physostigmine with a low initial burst over 1 week was achieved from RG 502 microparticles, which would be used as an injectable dosage form in our further animal studies.
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PMID:Design of physostigmine-loaded polymeric microparticles for pretreatment against exposure to organophosphate agents. 1252 68

(-)-Nicotine activates the hypothalamic-pituitary-adrenal axis via an activation of the brainstem catecholaminergic neurons in rats. The present study was undertaken to clarify the mechanisms involved in the (-)-nicotine-induced activation of brainstem catecholaminergic neurons in anesthetized rats. Physostigmine (a cholinesterase inhibitor) (0.31 and 0.77 micromol/animal, i.p.) dose-dependently elevated plasma corticosterone in the presence of scopolamine (a muscarinic receptor antagonist) (2.3 micromol/animal, i.p.). (-)-Nicotine (250 and 500 nmol/animal, i.c.v.) dose-dependently elevated plasma corticosterone with concomitant noradrenaline release in the hypothalamic paraventricular nucleus. The (-)-nicotine (500 nmol/animal, i.c.v.)-induced elevation of corticosterone was abolished by phentolamine (an alpha-adrenoceptor antagonist) (0.66 micromol/animal, i.c.v.), and attenuated by (+/-)-sotalol (a beta-adrenoceptor antagonist) (0.97 micromol/animal, i.c.v.). The (-)-nicotine-induced increases of plasma corticosterone and hypothalamic noradrenaline release were abolished either by hexamethonium (a nicotinic acetylcholine receptor antagonist) (1.8 micromol/animal, i.c.v.), CP-154,526 (butyl-ethyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine) (a selective CRF-1 receptor antagonist) (1.3 micromol/animal, i.c.v.) or indomethacin (a cyclooxygenase inhibitor) (1.2 micromol/animal, i.c.v.). These results suggest that (-)-nicotine elevates plasma corticosterone by CRF-1 receptor- and prostaglandin-mediated noradrenaline release in the paraventricular nucleus in rats.
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PMID:Extrahypothalamic corticotropin-releasing hormone mediates (-)-nicotine-induced elevation of plasma corticosterone in rats. 1289 41

The relative potencies of eserine and neostigmine were determined on three preparations of cholinesterase. Eserine was found to be twice as potent as neostigmine on the pseudocholinesterase of horse plasma, half as potent on the true cholinesterase of cat central nervous system, but twelve times as potent on the true cholinesterase prepared from the leech body wall. On the leech preparation, about ten times smaller concentrations of eserine than of neostigmine were required to potentiate the acetylcholine response, but after removal of the anticholinesterase from the bath fluid, the potentiation persisted much longer after neostigmine than after eserine. The greater sensitivity of the leech muscle to eserine is fully accounted for by the fact that its cholinesterase is more sensitive to eserine than to neostigmine. The longer lasting potentiation after neostigmine on the other hand suggests that this anticholinesterase becomes more firmly attached to the cholinesterase receptors in this muscle than does eserine.
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PMID:Comparison of the effects of eserine and neostigmine on the leech muscle preparation. 1353 79

A method has been developed for localizing sites of cholinesterase activity in rat cardiac muscle by electron microscopy. The method utilizes thiocholine esters as substrates, and is believed to be dependent on the reduction of ferricyanide to ferrocyanide by thiocholine released by enzymatic activity. The ferrocyanide thus formed is captured by copper to form fine, electron-opaque deposits of copper ferrocyanide, which sharply delineate sites of enzymatic activity at the ultrastructural level. Cholinesterase activity in formalin-fixed heart muscle was localized: (a) in longitudinal elements of the sarcoplasmic reticulum, but not in the T, or transverse, elements; and (b) in the A band, with virtually no activity noted in the M band, or in the H zone. The I band was also negative. No activity was detected in the sarcolemma, or in invaginations of the sarcolemma at the level of the Z band. The perinuclear element of the sarcoplasmic (endoplasmic) reticulum was frequently strongly positive. Activity at all sites was completely abolished by omitting the substrates, or by inhibition with eserine 10(-4)M and diisopropylfluorophosphate 10(-5)M. Eserine 10(-5)M completely inhibited reaction in the sarcoplasmic reticulum, and virtually abolished that in the A band. These observations, together with the use of the relatively specific substrates and suitable controls to eliminate non-enzymatic staining, indicate that cholinesterase activity was being demonstrated. The activity in rat heart against different substrates was that of non-specific cholinesterases, in accordance with biochemical data. The activity in the A band was considered to be probably due to myosincholinesterase. It is proposed that the localization of cholinesterases in myocardium at the ultrastructural level should be taken into account in considering the possible functions of these myocardial enzymes, and it is hoped that knowledge of their localization will open up new avenues of approach in considering their physiological role in myocardium, which at present is not definitely known.
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PMID:THE LOCALIZATION OF CHOLINESTERASE ACTIVITY IN RAT CARDIAC MUSCLE BY ELECTRON MICROSCOPY. 1422 10


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