Sample records for cholinesterases

  1. Cholinergic symptoms with low serum cholinesterase from therapeutic cholinesterase inhibitor toxicity.

    PubMed

    Leikin, Jerrold B; Braund, Victoria; DesLauris, Carol

    2014-07-01

    Although cholinesterase inhibitors have been frequently used in the treatment of Alzheimer disease, its effects on serum cholinesterase concentrations have been rarely described. We described significant depression of serum cholinesterase levels due to cholinesterase inhibitor toxicity from redundant use of donepezil and rivastigmine in a 78-year-old man. Recovery of serum cholinesterase level was noted upon drug discontinuation and cholinergic symptom resolution. Serum cholinesterase level can be used as a biomarker for central cholinesterase inhibitor toxicity.

  2. ACETYL CHOLINESTERASE AND BUTYRYL CHOLINESTERASE INhIBITORY ACTIVITIES OF ZALEYA PENTANDRA.

    PubMed

    Afzal, Samina; Chaudhry, Bashir Ahmad; Afzal, Khurram; Saeed, Javeria; Akash, Sajd Hamid; Qadir, Muhammad Imran

    2017-05-01

    The aim of this study was to reveal acetyl cholinesterase (AchE) and butyryl cholinesterase (BchE) inhibitory activities of Zaleya pentandra. The aerial parts of the plant were air, freeze-dried and powdered. The extraction was carried out with methanol at room temperature for 24 h. The extract was concentrated on rotavapor and fractioned by column chromatography. The isolation and purification afforded amorphous solid which was subjected to physical, chemical and spectroscopic techniques i.e., UV, IR, H-NMR, "C-NMR and HREI-MS for the structure elucidation of the isolated compound. The compound was concluded as "Pentandradione" a novel compound. AchE and BchE inhibitory activities were estimated. The result showed that the isolated extract possessed significant activity against butyryl cholinesterase as compared to standard eserine while the extract lacks acetyl cholinesterase inhibitory activity.

  3. Brain cholinesterase activities of passerine birds in forests sprayed with cholinesterase inhibiting insecticides

    USGS Publications Warehouse

    Zinkl, J.G.; Henny, C.J.; Shea, P.J.

    1979-01-01

    Brain cholinesterase activities were determined in passerines collected from northwestern forests that had been sprayed with trichlorfon, acephate, and carbaryl at 0.56, 1.13 and 2.26 kg/ha. Trichlorfon and carbaryl inhibited cholinesterase activity slightly in only a few birds, primarily canopy dwellers. In contrast, acephate caused marked inhibition of cholinesterase activity in nearly all birds collected. The inhibition was present even 33 days after spraying. Some birds from the acephate-sprayed forests exhibited clinical signs compatible with acute acetylcholinesterase inhibition.

  4. Cholinesterase-based biosensors.

    PubMed

    Štěpánková, Šárka; Vorčáková, Katarína

    2016-01-01

    Recently, cholinesterase-based biosensors are widely used for assaying anticholinergic compounds. Primarily biosensors based on enzyme inhibition are useful analytical tools for fast screening of inhibitors, such as organophosphates and carbamates. The present review is aimed at compilation of the most important facts about cholinesterase based biosensors, types of physico-chemical transduction, immobilization strategies and practical applications.

  5. [To the 80-anniversary of cholinesterase. The cholinesterase club in Sechenov Institute of Evolutionary Physiology and Biochemistry].

    PubMed

    Rozengart, E V; Basova, N E; Moralev, S N

    2012-01-01

    For the second half of the XX century, Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences was the center of the Russian cholinesterase investigations ("the Russian cholinesterase club"). The close cooperation with chemists-syntheticians of different scientific schools provided success and fruitfulness of this scientific search. All these years, there was preserved dualism of this investigation: a study of the mechanism of functioning and kinetics of cholinesterase catalysis as well as the comparative-enzymological character of studies of cholinesterases of the animals being at different levels of evolutionary development.

  6. Cholinesterase activity in Japanese quail dusted with carbaryl

    USGS Publications Warehouse

    Hill, E.F.

    1979-01-01

    Japanese quail (Coturnix coturnix japonica) were dusted with 5% carbaryl to determine if this topical treatment would alter plasma and brain cholinesterase activities. Within 6 hours after dusting, plasma cholinesterase activity was depressed compared with controls, the depression averaging 20% for females and 27% for males. By 24 hours the cholinesterase activity of females had returned to normal, but the cholinesterase activity of males remained depressed. Brain cholinesterase activity was not affected by the treatment, and there were no overt toxic signs.

  7. Distribution and determination of cholinesterases in mammals

    PubMed Central

    Holmstedt, Bo

    1971-01-01

    This paper reviews the distribution of cholinesterases in the central nervous system, the ganglia, the striated muscle, and the blood of mammals, and discusses the correlation between the histochemical localization and the function of neuronal cholinesterase. Different methods for the determination of cholinesterase levels are reviewed, with particular reference to their practical value for field work. The Warburg method and the Tintometer and Acholest colorimetric methods are compared on the basis of cholinesterase levels determined in normal persons and in those suffering from parathion intoxication. PMID:4999484

  8. Cholinesterases, a target of pharmacology and toxicology.

    PubMed

    Pohanka, Miroslav

    2011-09-01

    Cholinesterases are a group of serine hydrolases that split the neurotransmitter acetylcholine (ACh) and terminate its action. Of the two types, butyrylcholinesterase and acetylcholinesterase (AChE), AChE plays the key role in ending cholinergic neurotransmission. Cholinesterase inhibitors are substances, either natural or man-made that interfere with the break-down of ACh and prolong its action. Hence their relevance to toxicology and pharmacology. The present review summarizes current knowledge of the cholinesterases and their inhibition. Particular attention is paid to the toxicology and pharmacology of cholinesterase-related inhibitors such as nerve agents (e.g. sarin, soman, tabun, VX), pesticides (e.g. paraoxon, parathion, malathion, malaoxon, carbofuran), selected plants and fungal secondary metabolites (e.g. aflatoxins), drugs for Alzheimer's disease (e.g. huperzine, metrifonate, tacrine, donepezil) and Myasthenia gravis (e.g. pyridostigmine) treatment and other compounds (propidium, ethidium, decamethonium). The crucial role of the cholinesterases in neural transmission makes them a primary target of a large number of cholinesterase-inhibiting drugs and toxins. In pharmacology, this has relevance to the treatment of neurodegenerative disorders.

  9. Cholinesterase inhibitors from botanicals

    PubMed Central

    Ahmed, Faiyaz; Ghalib, Raza Murad; Sasikala, P.; Ahmed, K. K. Mueen

    2013-01-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disease, wherein a progressive loss of cholinergic synapses occurs in hippocampus and neocortex. Decreased concentration of the neurotransmitter, acetylcholine (ACh), appears to be critical element in the development of dementia, and the most appropriate therapeutic approach to treat AD and other form of dementia is to restore acetylcholine levels by inhibiting both major form of cholinesterase: Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Consequently, researches have focused their attention towards finding cholinesterase inhibitors from natural products. A large number of such inhibitors have been isolated from medicinal plants. This review presents a comprehensive account of the advances in field of cholinesterase inhibitor phytoconstituents. The structures of some important phytoconstituents (collected through www.Chemspider.com) are also presented and the scope for future research is discussed. PMID:24347920

  10. Cholinesterase inhibitors: a patent review (2007 - 2011).

    PubMed

    de los Ríos, Cristóbal

    2012-08-01

    Cholinesterase inhibitors participate in the maintenance of the levels of the neurotransmitter acetylcholine by inhibiting the enzymes implicated in its degradation, namely, butyrylcholinesterase and acetylcholinesterase. This pharmacological action has an important role in several diseases, including neurodegenerative diseases such as Alzheimer's. This article reviews recent advances in the development of cholinesterase enzyme inhibitors, covering the development of new chemical entities, new pharmaceutical formulations with known inhibitors or treatments in combination with other drug families. The development of cholinesterase inhibitors has to face several issues, including the fact that the principal indication for these drugs, Alzheimer's disease, is not currently believed to derivate from a cholinergic deficiency, although most of the drugs clinically used for these disease are cholinesterase inhibitors. Moreover, the adverse effects found when administering cholinesterase inhibitors limit their use in other diseases, such as gastrointestinal diseases, glaucoma, or analgesia.

  11. Composites of silica with immobilized cholinesterase incorporated into polymeric shell

    NASA Astrophysics Data System (ADS)

    Payentko, Victoriya; Matkovsky, Alexander; Matrunchik, Yulia

    2015-02-01

    Synthetic approaches for new nanocomposite materials with relatively high cholinesterase activity have been developed. The peculiarity of the formation of such systems is the introduction of cholinesterase into polymer with subsequent incorporation on the ready-made silica particles and into the polysiloxane matrixes during sol-gel synthesis. Evaluation of the cholinesterase activity has been fulfilled through the imitation of the acetylcholine chloride decomposition reaction. Values of activity for cholinesterase nanocomposites demonstrated in this work are higher than those for the native cholinesterase. The higher activity of cholinesterase contained in nanocomposites was found for those prepared using highly dispersed silica.

  12. Brain cDNA clone for human cholinesterase

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    McTiernan, C.; Adkins, S.; Chatonnet, A.

    1987-10-01

    A cDNA library from human basal ganglia was screened with oligonucleotide probes corresponding to portions of the amino acid sequence of human serum cholinesterase. Five overlapping clones, representing 2.4 kilobases, were isolated. The sequenced cDNA contained 207 base pairs of coding sequence 5' to the amino terminus of the mature protein in which there were four ATG translation start sites in the same reading frame as the protein. Only the ATG coding for Met-(-28) lay within a favorable consensus sequence for functional initiators. There were 1722 base pairs of coding sequence corresponding to the protein found circulating in human serum.more » The amino acid sequence deduced from the cDNA exactly matched the 574 amino acid sequence of human serum cholinesterase, as previously determined by Edman degradation. Therefore, our clones represented cholinesterase rather than acetylcholinesterase. It was concluded that the amino acid sequences of cholinesterase from two different tissues, human brain and human serum, were identical. Hybridization of genomic DNA blots suggested that a single gene, or very few genes coded for cholinesterase.« less

  13. The progress in the cholinesterase quantification methods.

    PubMed

    Holas, Ondrej; Musilek, Kamil; Pohanka, Miroslav; Kuca, Kamil

    2012-12-01

    Determination of acetylcholinesterase and butyrylcholinesterase activity has become an important tool in drug design and discovery as well as in medicine and toxicology. There are a large number of compounds that are able to modulate cholinesterase activity. These compounds can be used for pharmacological management of various disorders (e.g., Alzheimer's disease, myasthenia Gravis). Moreover, organophosphate poisoning is frequently diagnosed via a cholinesterase activity assay. This broad variety of methods has been developed over the past decades for cholinesterase activity quantification. This review provides a summary of the methods that are based on specific properties of cholinesterases and their interactions with native or artificial substrates. The authors also aim to provide an overview of different techniques used for the determination of quantitative cholinesterase activity. Specifically, the authors describe and discuss the manometric, potentiometric, titrimetric, photometric, fluorometric, and radioisotopic methods. Existing methods are able to cover most of the problems that arise during cholinesterase activity determination. Colorimetry according to Ellman has proved to be the most useful and versatile approach. It may be used in various protocols for the determination of pesticide or nerve agent exposure or for the development of new drugs. Its possible improvement lies in optimization of hemoglobin-rich samples. The progress of the most common methods (including Ellman) depends on miniaturization and modern physical platforms (e.g., optical fibers, chip methods, or nanotechnologies).

  14. 10th International Meeting on Cholinesterases

    DTIC Science & Technology

    2009-10-01

    NATIVE, PHOSPHYLATED AND AGED HUMAN ACETYLCHOLINESTERASE AND BUTYRYLCHOLINESTERASE Page 9 Zrinka Kovarik ( Zagreb , Croatia): OXIME-ASSISTED...REACTIVATION OF PHOSPHORYLATED BUTYRYLCHOLINESTERASE Goran Šinko ( Zagreb , Croatia): INTERACTIONS OF PYRIDINIUM OXIMES WITH ACETYLCHOLINESTERASE...OF CHOLINESTERASES IN THE BRAIN Ninoslav Mimica ( Zagreb , Croatia): THE CHOLINESTERASE INHIBITORS – CURRENT CLINICAL VIEW AND CROATIAN REALITY

  15. Comparative aspects of the purification and properties of cholinesterases

    PubMed Central

    Augustinsson, Klas-Bertil

    1971-01-01

    Recent years have seen great progress in the purification and characterization of cholinesterases. Investigation has indicated the existence of two principal groups: a fairly homogeneous group of acetylcholinesterases and a group of enzymes that utilize butyrylcholine, propionycholine, or benzoylcholine as substrates and that differ widely in their properties. This paper reviews the different types of cholinesterase and their sources, the importance of a proper choice of substrate in cholinesterase studies, methods for the purification of cholinesterases, and some of the properties of these enzymes. PMID:4938026

  16. Comparison of methods for measuring cholinesterase inhibition by carbamates

    PubMed Central

    Wilhelm, K.; Vandekar, M.; Reiner, E.

    1973-01-01

    The Acholest and tintometric methods are used widely for measuring blood cholinesterase activity after exposure to organophosphorus compounds. However, if applied for measuring blood cholinesterase activity in persons exposed to carbamates, the accuracy of the methods requires verification since carbamylated cholinesterases are unstable. The spectrophotometric method was used as a reference method and the two field methods were employed under controlled conditions. Human blood cholinesterases were inhibited in vitro by four methylcarbamates that are used as insecticides. When plasma cholinesterase activity was measured by the Acholest and spectrophotometric methods, no difference was found. The enzyme activity in whole blood determined by the tintometric method was ≤ 11% higher than when the same sample was measured by the spectrophotometric method. PMID:4541147

  17. CHOLINESTERASE IN DENERVATED END PLATES AND MUSCLE FIBRES

    PubMed Central

    Brzin, Miro; Majcen-Tkačev, Živa

    1963-01-01

    Parallel studies were made of cholinesterase activities and localizations in denervated rat and rabbit gastrocnemius muscle. Koelle's histochemical reaction was used for demonstrating the localization of cholinesterases. Enzyme activities in whole sliced muscle were measured by electrometric titration. The Cartesian ampulla-diver technique was used for cholinesterase activity determinations in end plate regions or in small pieces of the muscle fibre itself. No changes in the activity of cholinesterases (ChE) were found in the whole denervated muscle which would account for its chemical supersensitivity. The ChE distribution pattern was changed so that the end plate region became less active in the denervated muscle than in the normal one. The decrease in ChE activity in the end plates seems to be largely compensated for by an increase of this enzyme elsewhere in the muscle. A possible connection between the spatial spread of cholinesterase activity and the enlargement of the acetylcholine-sensitive surface is discussed. PMID:14086761

  18. Genomic clones for human cholinesterase

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Kott, M.; Venta, P.J.; Larsen, J.

    1987-05-01

    A human genomic library was prepared from peripheral white blood cells from a single donor by inserting an MboI partial digest into BamHI poly-linker sites of EMBL3. This library was screened using an oligolabeled human cholinesterase cDNA probe over 700 bp long. The latter probe was obtained from a human basal ganglia cDNA library. Of approximately 2 million clones screened with high stringency conditions several positive clones were identified; two have been plaque purified. One of these clones has been partially mapped using restriction enzymes known to cut within the coded region of the cDNA for human serum cholinesterase. Hybridizationmore » of the fragments and their sizes are as expected if the genomic clone is cholinesterase. Sequencing of the DNA fragments in M13 is in progress to verify the identify of the clone and the location of introns.« less

  19. [Methods for determination of cholinesterase activity].

    PubMed

    Dingová, D; Hrabovská, A

    2015-01-01

    Cholinesterases hydrolyze acetylcholine and thus they play a key role in a process of cholinergic neurotransmission. Changes in their activities are linked to many diseases (e.g Alzheimer disease, Parkinson disease, lipid disorders). Thus, it is important to determine their activity in a fast, simply and precise way. In this review, different approaches of studying cholinesterase activities (e.g pH-dependent, spectrophotometric, radiometric, histochemical methods or biosensors) are discussed. Comparisons, advantages or disadvantages of selected methods (e.g most widely used Ellman's assay, extremely sensitive Johnson Russell method or modern technique with golden nanoparticles) are presented. This review enables one to choose a suitable method for determination of cholinesterase activities with respect to laboratory equipment, type of analysis, pH, temperature scale or special conditions.

  20. Effects of Ionizing Radiation on Arylesterase and Cholinesterase.

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Augustinsson, Klas-Bertil; Jonsson, Gunnel; Sparrman, Berndt

    1961-01-01

    The effects of Co 60 gamma radiation on arylesterase and cholinesterase of human blood plasma were compared using solid preparations of purified enzymes containing various amounts of water. In the case of cholinesterase a water content of 12% exerted maximum protection against irradiation. Such a protection by water was not observed with arylesterase. Finally, in aqueous solutions cholinesterase was more resistant to irradiation by gamma rays than was arylesterase when irradiation was performed in an atmosphere of nitrogen.

  1. EFFECT OF GAMMA IRRADIATION AND AET ON RAT BLOOD CHOLINESTERASE

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Williams, M.W.; Baker, R.D.; Covill, R.W.

    1961-03-01

    Whole-body gamma irradiation in the rat produced significant whole-blood cholinesterase depression on the tenth day at a dosage level of 75 r. The levels tested when plotted and extrapolared indicated threshold changes in cholinesterase activity would be in the vicinity of 20 to 30 r. AET alone, while producing some mild cholinesterase depression, failed to protect whole-blood cholinesterase activity from the effects of gamma irradiation at the levels of agent and irradiation tested. (auth)

  2. Iminosugars as a new class of cholinesterase inhibitors.

    PubMed

    Decroocq, Camille; Stauffert, Fabien; Pamlard, Olivier; Oulaïdi, Farah; Gallienne, Estelle; Martin, Olivier R; Guillou, Catherine; Compain, Philippe

    2015-02-15

    To further extend the scope of iminosugar biological activity, a systematic structure-activity relationship investigation has been performed by synthesizing and evaluating as cholinesterase inhibitors a library of twenty-three iminoalditols with different substitutions and stereochemistry patterns. These compounds have been evaluated in vitro for the inhibition of cholinesterases (different sources of acetylcholinesterase and butyrylcholinesterase). Some compounds have IC50 values in the micromolar range and display significant inhibition selectivity for butyrylcholinesterase over acetylcholinesterase. These are the first examples of iminosugar-based inhibitors of cholinesterases. Copyright © 2015 Elsevier Ltd. All rights reserved.

  3. Natural genomic amplification of cholinesterase genes in animals.

    PubMed

    Chatonnet, Arnaud; Lenfant, Nicolas; Marchot, Pascale; Selkirk, Murray E

    2017-08-01

    Tight control of the concentration of acetylcholine at cholinergic synapses requires precise regulation of the number and state of the acetylcholine receptors, and of the synthesis and degradation of the neurotransmitter. In particular, the cholinesterase activity has to be controlled exquisitely. In the genome of the first experimental models used (man, mouse, zebrafish and drosophila), there are only one or two genes coding for cholinesterases, whereas there are more genes for their closest relatives the carboxylesterases. Natural amplification of cholinesterase genes was first found to occur in some cancer cells and in insect species subjected to evolutionary pressure by insecticides. Analysis of the complete genome sequences of numerous representatives of the various metazoan phyla show that moderate amplification of cholinesterase genes is not uncommon in molluscs, echinoderms, hemichordates, prochordates or lepidosauria. Amplification of acetylcholinesterase genes is also a feature of parasitic nematodes or ticks. In these parasites, over-production of cholinesterase-like proteins in secreted products and the saliva are presumed to have effector roles related to host infection. These amplification events raise questions about the role of the amplified gene products, and the adaptation processes necessary to preserve efficient cholinergic transmission. This is an article for the special issue XVth International Symposium on Cholinergic Mechanisms. © 2017 International Society for Neurochemistry.

  4. Research on cholinesterases in the Soviet Union and Russia: a historical perspective.

    PubMed

    Rozengart, Eugene V; Basova, Natalia E; Moralev, Serge N; Lushchekina, Sofya V; Masson, Patrick; Varfolomeev, Sergei D

    2013-03-25

    Research on cholinesterases and effects of their inhibition in the USSR and Russia since 1930-1940s till present is exposed in historical aspects. The first physiological and toxicological effects of cholinesterase inhibition were reported by Alexander Ginetsinsky during World War II, when academic institutions were evacuated from Leningrad to Kazan. The main scientific schools that initiated research on chemistry, enzymology and physiology of cholinesterases and their inhibitors were leaded by Alexandr and Boris Arbuzovs, Victor Rozengart, Viktor Yakovlev, Michael Michelson, Martin Kabachnik, Mikhail Voronkov, Ivan Knunyants, Alexandr Bretskin and others. They investigated the main physiological effects of cholinesterase inhibitors, and analyzed the catalytic mechanisms of cholinesterases and related enzymes. Their contributions are landmarks in the history of cholinesterase research. At the present time revival of research on cholinesterases in different universities and institutes is vivid, in particular at the Moscow State University, research institutes of Russian Academy of Sciences and Kazan Scientific Center. Copyright © 2013. Published by Elsevier Ireland Ltd.

  5. The enzymatic hydrolysis of imidazoleacryloylcholine (murexine) and imidazolepropionylcholine (dihydromurexine) by various cholinesterases

    PubMed Central

    Grelis, M. E.; Tabachnick, I. I. A.

    1957-01-01

    Several choline esters, including the imidazoleacryloyl and imidazolepropionyl compounds, have been hydrolysed by cholinesterases from various sources. The imidazolepropionyl ester was metabolized by cholinesterases obtained from human plasma, ox spleen, ox serum, and guinea-pig liver, but not by rat liver or bovine red cell cholinesterase. It is suggested the imidazolepropionylcholine or a closely related ester might be the natural substrate for “non-specific” cholinesterase. PMID:13460237

  6. Characterization of plasma cholinesterase in rabbit and evaluation of the inhibitory potential of diazinon.

    PubMed

    Oropesa, Ana Lourdes; Pérez-López, Marcos; Soler, Francisco

    2014-02-01

    Several studies indicate that more than one cholinesterase form may be present in the blood of mammals. In this study the predominant plasma cholinesterase activity, the physiological cholinesterase activity as well as cholinesterase sex-dependent changes in non-exposed individuals of rabbit have been established. Plasma cholinesterase was characterized using three substrates (acetylthiocholine iodide, propionylthiocholine iodide, and S-butyrylthiocholine iodide) and three cholinesterase inhibitors (eserine sulfate, BW284C51 and iso-OMPA). The results indicated that propionylthiocholine was the preferred substrate by plasma cholinesterase followed by acetylthiocholine and butyrylthiocholine, and the predominant enzymatic activity was acetylcholinesterase. Physiological plasma cholinesterase activity was 198.9 ± 5.8 nmol/min/ml for male and 205.2 ± 5.0 nmol/min/ml for female using acetylthiocholine as substrate. Thus, sex had no significant effect on the physiological cholinesterase activity (p>0.05). In addition, the in vivo and in vitro sensitivity of plasma cholinesterase to diazinon was also investigated. In rabbits exposed to single doses of diazinon (25 or 125 mg/kg) the higher inhibitions of plasma cholinesterase were reached 9h after oral administration (53% and 87% inhibition, respectively). Cholinesterase activity significantly recovered up to values similar to pre-administration between 3 and 7d depending on the administered dose and sex of the animals. Plasma cholinesterase activity decreased to 24%, 53% and 74% of the initial activity at 9h of in vitro exposure to 1.25, 3.13 and 6.25mg/l of diazinon, respectively, and it remained steadily depressed throughout the experimental period (10d). This study has demonstrated the sensitivity of cholinesterase activity in plasma of rabbits following both in vivo and in vitro exposure to sub-lethal concentrations of diazinon. © 2013 Published by Elsevier Inc.

  7. Whole Blood Cholinesterase Activity in 20 Species of Wild Birds.

    PubMed

    Horowitz, Igal H; Yanco, Esty G; Landau, Shmulik; Nadler-Valency, Rona; Anglister, Nili; Bueller-Rosenzweig, Ariela; Apelbom-Halbersberg, Tal; Cuneah, Olga; Hanji, Vera; Bellaiche, Michel

    2016-06-01

    Clinical signs of organophosphate and carbamate intoxication in wild birds can be mistaken for those of other diseases, thus potentially delaying diagnosis and implementation of life-saving treatment. The objective of this study was to determine the reference interval for blood cholinesterase activity in 20 different wild avian species from 7 different orders, thereby compiling a reference database for wildlife veterinarians. Blood was collected from birds not suspected of having organophosphate or carbamate toxicosis, and the modified Michel method, which determines the change in blood pH that directly correlates with cholinesterase activity, was used to measure blood cholinesterase levels. Results of change in blood pH values ranged from 0.11 for the white-tailed eagle ( Haliaeetus albicilla ) to 0.90 for the honey buzzard ( Pernis apivorus ). The results showed that even within the same family, interspecies differences in normal cholinesterase blood activity were not uncommon. The findings emphasized the importance of determining reference intervals for avian blood cholinesterase activity at the species level.

  8. Cholinesterases as biomarkers for parasympathetic dysfunction and inflammation-related disease.

    PubMed

    Shenhar-Tsarfaty, Shani; Berliner, Shlomo; Bornstein, Natan M; Soreq, Hermona

    2014-07-01

    Accumulating evidence suggests parasympathetic dysfunction and elevated inflammation as underlying processes in multiple peripheral and neurological diseases. Acetylcholine, the main parasympathetic neurotransmitter and inflammation regulator, is hydrolyzed by the two closely homologous enzymes, acetylcholinesterase and butyrylcholinesterase (AChE and BChE, respectively), which are also expressed in the serum. Here, we consider the potential value of both enzymes as possible biomarkers in diseases associated with parasympathetic malfunctioning. We cover the modulations of cholinesterase activities in inflammation-related events as well as by cholinesterase-targeted microRNAs. We further discuss epigenetic control over cholinesterase gene expression and the impact of single-nucleotide polymorphisms on the corresponding physiological and pathological processes. In particular, we focus on measurements of circulation cholinesterases as a readily quantifiable readout for changes in the sympathetic/parasympathetic balance and the implications of changes in this readout in health and disease. Taken together, this cumulative know-how calls for expanding the use of cholinesterase activity measurements for both basic research and as a clinical assessment tool.

  9. Thioesters for the in vitro evaluation of agents to image brain cholinesterases.

    PubMed

    Macdonald, Ian R; Jollymore, Courtney T; Reid, G Andrew; Pottie, Ian R; Martin, Earl; Darvesh, Sultan

    2013-06-01

    Cholinesterases are associated with pathology characteristic of conditions such as Alzheimer's disease and are therefore, considered targets for neuroimaging. Ester derivatives of N-methylpiperidinol are promising potential imaging agents; however, methodology is lacking for evaluating these compounds in vitro. Here, we report the synthesis and evaluation of a series of N-methylpiperidinyl thioesters, possessing comparable properties to their corresponding esters, which can be directly evaluated for cholinesterase kinetics and histochemical distribution in human brain tissue. N-methylpiperidinyl esters and thioesters were synthesized and they demonstrated comparable cholinesterase kinetics. Furthermore, thioesters were capable, using histochemical method, to visualize cholinesterase activity in human brain tissue. N-methylpiperidinyl thioesters can be rapidly evaluated for cholinesterase kinetics and visualization of enzyme distribution in brain tissue which may facilitate development of cholinesterase imaging agents for application to conditions such as Alzheimer's disease.

  10. Distribution of cholinesterases in insects*

    PubMed Central

    Booth, G. M.; Lee, An-Horng

    1971-01-01

    The study of toxicology and other related fields has been largely based on in vitro techniques. These methods have provided quantitative information on the effects of inhibitors on enzymes, but none on the localized effects of inhibitors on selected sites of action within the animal. Histochemical study of frozen sections does provide data on the site of action of toxicants. The utility of histochemistry in conjunction with in vitro methods is discussed. The substrates acetylthiocholine and phenyl thioacetate were utilized in demonstrating cholinesterase. Neither substrate penetrated well into freshly dissected nerve cord preparations, but both compounds were hydrolysed by sectioned tissue. The leaving group of phenyl thioacetate was demonstrated to be benzenethiol. In general, acetylthiocholine was hydrolysed slightly more rapidly by insect cholinesterases. A unique cholinesterase was found in motor end-plates of cricket muscle, which hydrolyses acetylthiocholine and which was inhibited by physostigmine. No other insect muscle preparation showed this activity. Topical application of insecticides showed that a vital site of action in flies is the peripheral area of the thoracic ganglia and that in crickets the brain and nerve cord are involved at knock-down. Kinetic data indicate that acetylthiocholine has a greater affinity than does phenyl thioacetate for a variety of enzyme sources. Ultrastructural evidence shows that cholinesterases that hydrolyse acetylthiocholine are membrane-bound. Phenyl thioacetate was found to be useful as a model in designing new insecticides. ImagesFig. 5Fig. 6Fig. 7Fig. 8Fig. 13Fig. 14Fig. 15Fig. 16Fig. 9Fig. 10Fig. 11Fig. 12Fig. 1Fig. 2Fig. 3Fig. 4Fig. 17Fig. 18Fig. 19 PMID:5315359

  11. Cholinesterase Inhibitors for Lewy Body Disorders: A Meta-Analysis

    PubMed Central

    Yasue, Ichiro; Iwata, Nakao

    2016-01-01

    Background: We performed a meta-analysis of cholinesterase inhibitors for patients with Lewy body disorders, such as Parkinson’s disease, Parkinson’s disease dementia, and dementia with Lewy bodies. Methods: The meta-analysis included only randomized controlled trials of cholinesterase inhibitors for Lewy body disorders. Results: Seventeen studies (n = 1798) were assessed. Cholinesterase inhibitors significantly improved cognitive function (standardized mean difference [SMD] = −0.53], behavioral disturbances (SMD = −0.28), activities of daily living (SMD = −0.28), and global function (SMD = −0.52) compared with control treatments. Changes in motor function were not significantly different from control treatments. Furthermore, the cholinesterase inhibitor group had a higher all-cause discontinuation (risk ratio [RR] = 1.48, number needed to harm [NNH] = 14), discontinuation due to adverse events (RR = 1.59, NNH = 20), at least one adverse event (RR = 1.13, NNH = 11), nausea (RR = 2.50, NNH = 13), and tremor (RR = 2.30, NNH = 20). Conclusions: Cholinesterase inhibitors appear beneficial for the treatment of Lewy body disorders without detrimental effects on motor function. However, a careful monitoring of treatment compliance and side effects is required. PMID:26221005

  12. Development of acetophenone ligands as potential neuroimaging agents for cholinesterases.

    PubMed

    Jollymore-Hughes, Courtney T; Pottie, Ian R; Martin, Earl; Rosenberry, Terrone L; Darvesh, Sultan

    2016-11-01

    Association of cholinesterase with β-amyloid plaques and tau neurofibrillary tangles in Alzheimer's disease offers an opportunity to detect disease pathology during life. Achieving this requires development of radiolabelled cholinesterase ligands with high enzyme affinity. Various fluorinated acetophenone derivatives bind to acetylcholinesterase with high affinity, including 2,2,2-trifluoro-1-(3-dimethylaminophenyl)ethanone (1) and 1-(3-tert-butylphenyl)-2,2,2-trifluoroethanone (2). Such compounds also offer potential for incorporation of radioactive fluorine ( 18 F) for Positron Emission Tomography (PET) imaging of cholinesterases in association with Alzheimer's disease pathology in the living brain. Here we describe the synthesis of two meta-substituted chlorodifluoroacetophenones using a Weinreb amide strategy and their rapid conversion to the corresponding trifluoro derivatives through nucleophilic substitution by fluoride ion, in a reaction amenable to incorporating 18 F for PET imaging. In vitro kinetic analysis indicates tight binding of the trifluoro derivatives to cholinesterases. Compound 1 has a K i value of 7nM for acetylcholinesterase and 1300nM for butyrylcholinesterase while for compound 2 these values are 0.4nM and 26nM, respectively. Tight binding of these compounds to cholinesterase encourages their development for PET imaging detection of cholinesterase associated with Alzheimer's disease pathology. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. Biological Studies in Childhood Schizophrenia: Plasma and RBC Cholinesterase Activity

    ERIC Educational Resources Information Center

    Lucas, Alexander R.; And Others

    1971-01-01

    A comparison of plasma (pseudo) cholinesterase and erythrocyte (true) cholinesterase activity in 16 male childhood schizophrenic patients and 16 male nonpsychotic hospitalized controls revealed no significant differences between the two groups. (Author)

  14. [The reversible inhibition of cholinesterases from different biological sources by phosphonium betaines].

    PubMed

    Zhuzhovskiĭ, Iu G; Kuznetsova, L P; Sochilina, E E; Dmitrieva, E N; Gololobov, Iu G; Bykovskaia, E Iu

    1996-01-01

    The action of some phosphonium betains on cholinesterases from different biological sources has been studied. It has been shown, that all studied betains are reversible inhibitors of cholinesterase hydrolysis of acetyltiocholine. Inhibiting action of these compounds on acetylcholinesterases is about ten times weaker that of the majority of known phosphonium salts, while their action on butyrylcholinesterases has no peculiarities. There were found certain differences for each betain compounds in their action on cholinesterases from different biological sources. These results may be used for detail classification of cholinesterases and allow to extend knowledge in comparative enzymology.

  15. Evolution of cholinesterases in the animal kingdom.

    PubMed

    Pezzementi, Leo; Chatonnet, Arnaud

    2010-09-06

    Cholinesterases emerged from a family of enzymes and proteins with adhesion properties. This family is absent in plants and expanded in multicellular animals. True cholinesterases appeared in triploblastic animals together with the cholinergic system. Lineage specific duplications resulted in two acetylcholinesterases in most hexapods and in up to four genes in nematodes. In vertebrates the duplication leading to acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) is now considered to be an ancient event which occurred before the split of osteichthyes. The product of one or the other of the paralogues is responsible for the physiological hydrolysis of acetylcholine, depending on the species lineage and tissue considered. The BChE gene seems to have been lost in some fish lineages. The complete genome of amphioxus (Branchiostoma floridae: cephalochordate) contains a large number of duplicated genes or pseudogenes of cholinesterases. Sequence comparison and tree constructions raise the question of considering the atypical ChE studied in this organism as a representative of ancient BChE. Thus nematodes, arthropods, annelids, molluscs, and vertebrates typically possess two paralogous genes coding for cholinesterases. The origin of the duplication(s) is discussed. The mode of attachment through alternative C-terminal coding exons seems to have evolved independently from the catalytic part of the gene. Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.

  16. Use of procainamide gels in the purification of human and horse serum cholinesterases.

    PubMed Central

    Ralston, J S; Main, A R; Kilpatrick, B F; Chasson, A L

    1983-01-01

    Two large-scale methods based primarily on the use of procainamide-Sepharose gels were developed for the purification of horse and human serum non-specific cholinesterases. With method I, the procainamide-Sepharose 4B gel was used in the first step to handle large volumes of serum. With method II, the procainamide-Sepharose 4B gel was used in the final step to obtain pure enzyme. Although both methods gave electrophoretically pure cholinesterase preparations in good yields, they were significantly more efficient at purifying the horse enzyme than the human enzyme. To study this problem, the relative binding of human and horse cholinesterases to procainamide-, methylacridinium (MAC)-, m-trimethylammoniophenyl (m-PTA)- and p-trimethylammoniophenyl (p-PTA)-Sepharose 4B gels were measured, by using two approaches. In one, binding was measured by a procedure involving equilibration of pure cholinesterase in a small volume of diluted gel slurry (4%, v/v). A partially purified preparation of Electrophorus acetylcholinesterase was included. Pure human cholinesterase bound consistently more tightly to each of the gels than did horse cholinesterase, and the acetylcholinesterase appeared to bind the gels 10-100 times more tightly than did the non-specific cholinesterases. The order of binding for the cholinesterases, beginning with the tightest, was: procainamide-Sepharose 4B, MAC-Sepharose 4B, p-PTA-Sepharose 4B and m-PTA-Sepharose 4B. For the acetylcholinesterase the order was: MAC-Sepharose 4B, procainamide-Sepharose 4B, p-PTA-Sepharose 4B and m-PTA-Sepharose 4B. The second approach involved passing native sera or partially purified sera fractions through 1 ml test columns of each of the four affinity gels to determine their retention capacity for the cholinesterases. With these impure samples, the MAC-Sepharose 4B gels proved superior to the procainamide-Sepharose 4B gels at retaining human cholinesterase, but the opposite was true for the horse cholinesterase. PMID

  17. Exposure of nonbreeding migratory shorebirds to cholinesterase-inhibiting contaminants in the western hemisphere

    USGS Publications Warehouse

    Strum, K.M.; Hooper, M.J.; Johnson, K.A.; Lanctot, Richard B.; Zaccagnini, M.E.; Sandercock, B.K.

    2010-01-01

    Migratory shorebirds frequently forage and roost in agricultural habitats, where they may be exposed to cholinesterase-inhibiting pesticides. Exposure to organophosphorus and carbamate compounds, common anti-cholinesterases, can cause sublethal effects, even death. To evaluate exposure of migratory shorebirds to organophosphorus and carbamates, we sampled birds stopping over during migration in North America and wintering in South America. We compared plasma cholinesterase activities and body masses of individuals captured at sites with no known sources of organophosphorus or carbamates to those captured in agricultural areas where agrochemicals were recommended for control of crop pests. In South America, plasma acetylcholinesterase and butyrylcholinesterase activity in Buff-breasted Sandpipers was lower at agricultural sites than at reference sites, indicating exposure to organophosphorus and carbamates. Results of plasma cholinesterase reactivation assays and foot-wash analyses were inconclusive. A meta-analysis of six species revealed no widespread effect of agricultural chemicals on cholinesterase activity. however, four of six species were negative for acetylcholinesterase and one of six for butyrylcholinesterase, indicating negative effects of pesticides on cholinesterase activity in a subset of shorebirds. Exposure to cholinesterase inhibitors can decrease body mass, but comparisons between treatments and hemispheres suggest that agrochemicals did not affect migratory shorebirds' body mass. Our study, one of the first to estimate of shorebirds' exposure to cholinesterase-inhibiting pesticides, suggests that shorebirds are being exposed to cholinesterase- inhibiting pesticides at specific sites in the winter range but not at migratory stopover sites. future research should examine potential behavioral effects of exposure and identify other potential sitesand levels of exposure. ?? The Cooper Ornithological Society 2010.

  18. Cholinesterase Inhibitors and Hospitalization for Bradycardia: A Population-Based Study

    PubMed Central

    Park-Wyllie, Laura Y.; Mamdani, Muhammad M.; Li, Ping; Gill, Sudeep S.; Laupacis, Andreas; Juurlink, David N.

    2009-01-01

    Background Cholinesterase inhibitors are commonly used to treat dementia. These drugs enhance the effects of acetylcholine, and reports suggest they may precipitate bradycardia in some patients. We aimed to examine the association between use of cholinesterase inhibitors and hospitalization for bradycardia. Methods and Findings We examined the health care records of more than 1.4 million older adults using a case-time-control design, allowing each individual to serve as his or her own control. Case patients were residents of Ontario, Canada, aged 67 y or older hospitalized for bradycardia between January 1, 2003 and March 31, 2008. Control patients (3∶1) were not hospitalized for bradycardia, and were matched to the corresponding case on age, sex, and a disease risk index. All patients had received cholinesterase inhibitor therapy in the 9 mo preceding the index hospitalization. We identified 1,009 community-dwelling older persons hospitalized for bradycardia within 9 mo of using a cholinesterase inhibitor. Of these, 161 cases informed the matched analysis of discordant pairs. Of these, 17 (11%) required a pacemaker during hospitalization, and six (4%) died prior to discharge. After adjusting for temporal changes in drug utilization, hospitalization for bradycardia was associated with recent initiation of a cholinesterase inhibitor (adjusted odds ratio [OR] 2.13, 95% confidence interval [CI] 1.29–3.51). The risk was similar among individuals with pre-existing cardiac disease (adjusted OR 2.25, 95% CI 1.18–4.28) and those receiving negative chronotropic drugs (adjusted OR 2.34, 95% CI 1.16–4.71). We found no such association when we replicated the analysis using proton pump inhibitors as a neutral exposure. Despite hospitalization for bradycardia, more than half of the patients (78 of 138 cases [57%]) who survived to discharge subsequently resumed cholinesterase inhibitor therapy. Conclusions Among older patients, initiation of cholinesterase inhibitor

  19. Plasma cholinesterase activity of rats, western grey kangaroos, alpacas, sheep, cattle, and horses.

    PubMed

    Mayberry, Chris; Mawson, Peter; Maloney, Shane K

    2015-01-01

    Plasma cholinesterase activity levels of various species may be of interest to toxicologists or pathologists working with chemicals that interfere with the activity of plasma cholinesterase. We used a pH titration method to measure the plasma cholinesterase activity of six mammalian species. Plasma cholinesterase activity varied up to 50-fold between species: sheep (88 ± 45 nM acetylcholine degraded per ml of test plasma per minute), cattle (94 ± 35), western grey kangaroos (126 ± 92), alpaca (364 ± 70), rats (390 ± 118) and horses (4539 ± 721). We present a simple, effective technique for the assay of plasma cholinesterase activity levels from a range of species. Although labour-intensive, it requires only basic laboratory equipment. Copyright © 2015 Elsevier Inc. All rights reserved.

  20. Serum cholinesterase is an important prognostic factor in chronic heart failure.

    PubMed

    Sato, Takamasa; Yamauchi, Hiroyuki; Suzuki, Satoshi; Yoshihisa, Akiomi; Yamaki, Takayoshi; Sugimoto, Koichi; Kunii, Hiroyuki; Nakazato, Kazuhiko; Suzuki, Hitoshi; Saitoh, Shu-ichi; Takeishi, Yasuchika

    2015-03-01

    We determine the importance of indicators of nutrition including lymphocyte, total protein, albumin, cholinesterase and body mass index, and compare the prognostic significance in chronic heart failure (CHF). We examined consecutive 465 CHF patients (376 males, age 62 ± 14 years) who underwent cardiopulmonary exercise testing, echocardiography and blood examination including indicators of nutrition at the same time in our hospital. The patients were followed up [median period 766 days (interquartile range 500-1060)] to register cardiac deaths and rehospitalization due to worsening heart failure. There were 180 cardiac events during the follow-up periods. Patients with cardiac events had lower cholinesterase level than those without events (P < 0.001). On the receiver operating characteristic analysis, the best cut-off value for cholinesterase was 240 U/l (area under the curve 0.720). In the Kaplan-Meier analysis, patients with cholinesterase <240 U/l had significantly higher cardiac event rates than those with cholinesterase >240 U/l. Multivariable Cox proportional hazards model demonstrated that NYHA class III [hazard ratio (HR): 1.688, 95 % confidence interval (CI) 1.062-2.684, P = 0.027], eGFR (HR: 0.983, 95 % CI 0.971-0.995, P = 0.006), sodium concentration (HR: 0.947, 95 % CI 0.897-0.999, P < 0.046), log BNP (HR: 1.880, 95 % CI 1.509-2.341, P < 0.001), cholinesterase (HR: 0.996, 95 % CI 0.993-0.998, P = 0.002) and exertional periodic breathing (HR: 1.619, 95 % CI 1.098-2.388, P = 0.015) were independent factors to predict adverse clinical outcomes. Serum cholinesterase level was an important prognostic factor in CHF.

  1. Amino acid sequence of human cholinesterase. Annual report, 30 September 1984-30 September 1985

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Lockridge, O.

    1985-10-01

    The active-site serine residue is located 198 amino acids from the N-terminal. The active-site peptide was isolated from three different genetic types of human serum cholinesterase: from usual, atypical, and atypical-silent genotypes. It was found that the amino acid sequence of the active-site peptide was identical in all three genotypes. Comparison of the complete sequences of cholinesterase from human serum and acetylcholinesterase from the electric organ of Torpedo californica shows an identity of 53%. Cholinesterase is of interest to the Department of Defense because cholinesterase protects against organophosphate poisons of the type used in chemical warfare. The structural results presentedmore » here will serve as the basis for cloning the gene for cholinesterase. The potential uses of large amounts of cholinesterase would be for cleaning up spills of organophosphates and possibly for detoxifying exposed personnel.« less

  2. Genetic variants of human serum cholinesterase influence metabolism of the muscle relaxant succinylcholine.

    PubMed

    Lockridge, O

    1990-01-01

    People with genetic variants of cholinesterase respond abnormally to succinylcholine, experiencing substantial prolongation of muscle paralysis with apnea rather than the usual 2-6 min. The structure of usual cholinesterase has been determined including the complete amino acid and nucleotide sequence. This has allowed identification of altered amino acids and nucleotides. The variant most frequently found in patients who respond abnormally to succinylcholine is atypical cholinesterase, which occurs in homozygous form in 1 out of 3500 Caucasians. Atypical cholinesterase has a single substitution at nucleotide 209 which changes aspartic acid 70 to glycine. This suggests that Asp 70 is part of the anionic site, and that the absence of this negatively charged amino acid explains the reduced affinity of atypical cholinesterase for positively charged substrates and inhibitors. The clinical consequence of reduced affinity for succinylcholine is that none of the succinylcholine is hydrolyzed in blood and a large overdose reaches the nerve-muscle junction where it causes prolonged muscle paralysis. Silent cholinesterase has a frame shift mutation at glycine 117 which prematurely terminates protein synthesis and yields no active enzyme. The K variant, named in honor of W. Kalow, has threonine in place of alanine 539. The K variant is associated with 33% lower activity. All variants arise from a single locus as there is only one gene for human cholinesterase (EC 3.1.1.8). Comparison of amino acid sequences of esterases and proteases shows that cholinesterase belongs to a new family of serine esterases which is different from the serine proteases.

  3. Potential association of reduced cholinesterase activity with Trypanosoma evansi pathogenesis in buffaloes.

    PubMed

    Singh, Shanker K; Singh, Vivek K; Yadav, Brajesh K; Nakade, Udayraj P; Kumari, Priyambada; Srivastava, Mukesh K; Sharma, Abhishek; Choudhary, Soumen; Swain, Dilip; Garg, Satish K

    2016-07-30

    The present study aimed to investigate the association of cholinesterase activity with trypanosomosis in buffaloes. Thirty-three clinical cases of trypanosomosis in water buffaloes, found positive for trypomastigotes of T. evansi on blood smear examination, were divided into two groups based on clinical manifestations. Twenty diseased buffaloes revealing only common clinical signs were allocated to Group I, while the remaining 13 buffaloes showing common clinical manifestations along with neurological disturbances were allocated to Group II. Twelve clinically healthy buffaloes, free from any haemoprotozoa infection, were kept as healthy control (Group III). Blood samples were collected from buffaloes of all three groups to determine serum cholinesterase activity. Compared to buffaloes of healthy control group, cholinesterase activity in T. evansi-infected buffaloes of Group I and II was significantly (P<0.001) lower. However, no significant difference was observed in cholinesterase activity between the T. evansi-infected buffaloes exhibiting neurological disorders and no neurological disorders. Summing up, reduced cholinesterase activity seems to be associated with the pathogenesis of natural T. evansi infection and its clinical manifestations in buffaloes possibly by evading immune response. Further studies are warranted on association of cholinesterase activity in T. evansi-infected buffaloes with neurological disorders. Copyright © 2016 Elsevier B.V. All rights reserved.

  4. Behavioral changes and cholinesterase activity of rats acutely treated with propoxur.

    PubMed

    Thiesen, F V; Barros, H M; Tannhauser, M; Tannhauser, S L

    1999-01-01

    Early assessment of neurological and behavioral effects is extremely valuable for early identification of intoxications because preventive measures can be taken against more severe or chronic toxic consequences. The time course of the effects of an oral dose of the anticholinesterase agent propoxur (8.3 mg/kg) was determined on behaviors displayed in the open-field and during an active avoidance task by rats and on blood and brain cholinesterase activity. Maximum inhibition of blood cholinesterase was observed within 30 min after administration of propoxur. The half-life of enzyme-activity recovery was estimated to be 208.6 min. Peak brain cholinesterase inhibition was also detected between 5 and 30 min of the pesticide administration, but the half-life for enzyme activity recovery was much shorter, in the range of 85 min. Within this same time interval of the enzyme effects, diminished motor and exploratory activities and decreased performance of animals in the active avoidance task were observed. Likewise, behavioral normalization after propoxur followed a time frame similar to that of brain cholinesterase. These data indicate that behavioral changes that occur during intoxication with low oral doses of propoxur may be dissociated from signs characteristic of cholinergic over-stimulation but accompany brain cholinesterase activity inhibition.

  5. Weight Loss Associated with Cholinesterase Inhibitors In Patients With Dementia in a National Healthcare System

    PubMed Central

    Sheffrin, Meera; Miao, Yinghui; Boscardin, W. John; Steinman, Michael A.

    2016-01-01

    Background/Objectives Inconsistent data from randomized trials suggest cholinesterase inhibitors may cause weight loss. We sought to determine if the initiation of cholinesterase inhibitors is associated with significant weight loss in a real-word clinical setting. Design Retrospective cohort study from 2007-2010, comparing weight loss in patients with dementia newly prescribed cholinesterase inhibitors and patients newly prescribed other chronic medications Setting National Veterans Affairs (VA) data Participants Patients 65 years or older with a diagnosis of dementia who received a new prescription for a cholinesterase inhibitor or other new other chronic medication. Measurements The primary outcome was time to 10 pound weight loss over 12 months. We used propensity score matching patients to control for the likelihood of receiving a cholinesterase inhibitor based on baseline characteristics. Data were analyzed in a priori defined subgroups by age, comorbid burden, and initial weight. Results Of 6,504 patients that met study criteria, 1188 patients started on cholinesterase inhibitors were matched to 2189 patients started on other medications. The propensity-matched cohorts were well balanced on baseline covariates. Patients initiated on cholinesterase inhibitors had a higher risk of weight loss compared to matched controls at 12 months, HR 1.23 (95% CI 1.07 - 1.41). At twelve months, 29.3% of patients on cholinesterase inhibitors had experienced weight loss compared to 22.8% of non-users, corresponding to a number needed to harm of 21.2 (95% CI 12.5 – 71.4) over one year. There were no significant differences across subgroups. Conclusion Patients with dementia started on cholinesterase inhibitors had a higher risk of clinically significant weight loss over a 12-month period compared to matched controls. These results are consistent with the available data from randomized controlled trials. Clinicians should consider the risk of weight loss when prescribing

  6. Serum Cholinesterase Is Inversely Associated with Body Weight Change in Men Undergoing Routine Health Screening.

    PubMed

    Oda, Eiji

    2015-01-01

    The purpose of this study is to investigate the relationships between serum cholinesterase and body weight change, in addition to incident obesity defined as a body mass index (BMI) of 25 kg/m(2) or greater. A retrospective 5-year follow-up study was conducted. The crude incidence and hazard ratios (HRs) of obesity adjusted for the BMI and other confounders were calculated for cholinesterase quartiles in 1,412 men and 921 women. Partial correlation coefficients (PCCs) were calculated between cholinesterase and changes in the BMI during the 5-year follow-up period adjusted for age and other confounders and the change in the BMI were compared among cholinesterase quartiles in 1,223 men and 681 women. During the 5-year follow-up period, 149 men (10.6%) and 65 women (7.1%) developed obesity. The adjusted HRs of obesity decreased, although the crude incidence of obesity increased along the quartiles of cholinesterase in men. The adjusted HRs of obesity for the first (lowest), second and third quartiles of cholinesterase were 2.02 (p=0.006), 1.45 (p=0.122), and 1.28 (p=0.265), respectively compared with the highest quartile in men. The PCC between the baseline level of cholinesterase and change in the BMI was -0.16 (p<0.001) in men. The mean changes in BMI for 5 years were 0.31 kg/m(2), 0.17 kg/m(2), 0.01 kg/m(2) and -0.04 kg/m(2), respectively in the first, second, third and fourth quartiles of cholinesterase in men (p=0.005). Neither incident obesity nor weight gain was significantly associated with cholinesterase in women. The serum cholinesterase level was inversely associated with body weight change, as well as incident obesity, after adjusted for the BMI in men.

  7. Effects of cholinesterase inhibitors on the activities and protein levels of cholinesterases in the cerebrospinal fluid of patients with Alzheimer's disease: a review of recent clinical studies.

    PubMed

    Darreh-Shori, T; Soininen, H

    2010-02-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive decline associated with a deficit in cholinergic function. Inhibitors of acetylcholinesterase (AChE) and/or butyrylcholinesterase (BuChE), such as donepezil, galantamine or rivastigmine, are widely prescribed as symptomatic treatments for AD. These agents exhibit a wide variation in their pharmacological properties. Here we review clinical data from 1998 to 2009 investigating the effect of different cholinesterase inhibitor treatments on the levels and activities of cholinesterases in the cerebrospinal fluid (CSF) of AD patients. These studies suggest that treatment with rapidly-reversible cholinesterase inhibitors (e.g. donepezil, galantamine, tacrine) are associated with marked and significant upregulation of AChE activities and protein levels in the CSF of AD patients. In contrast, pseudo-irreversible cholinesterase inhibition (e.g. rivastigmine) is associated with a significant decrease in both CSF AChE and BuChE activities, with no upregulation of CSF protein levels. Additionally, donepezil is associated with a decrease in the level of the AChE-R isoform relative to the synaptic AChE-S isoform, whereas rivastigmine seems to increase this ratio. These findings suggest that these agents exert different effects on CSF cholinesterases. The clinical effects of these pharmacological differences are yet to be fully established.

  8. Application of brain cholinesterase reactivation to differentiate between organophosphorus and carbamate pesticide exposure in wild birds

    USGS Publications Warehouse

    Smith, M.R.; Thomas, N.J.; Hulse, C.

    1995-01-01

    Brain cholinesterase activity was measured to evaluate pesticide exposure in wild birds. Thermal reactivation of brain cholinesterase was used to differentiate between carbamate and organophosphorus pesticide exposure. Brain cholinesterase activity was compared with gas chromatography and mass spectrometry of stomach contents. Pesticides were identified and confirmed in 86 of 102 incidents of mortality from 29 states within the USA from 1986 through 1991. Thermal reactivation of cholinesterase activity was used to correctly predict carbamates in 22 incidents and organophosphates in 59 incidents. Agreement (P < 0.001) between predictions based on cholinesterase activities and GC/MS results was significant.

  9. Selectivity of phenothiazine cholinesterase inhibitors for neurotransmitter systems.

    PubMed

    Darvesh, Sultan; Macdonald, Ian R; Martin, Earl

    2013-07-01

    Synthetic derivatives of phenothiazine have been used for over a century as well-tolerated drugs against a variety of human ailments from psychosis to cancer. This implies a considerable diversity in the mechanisms of action produced by structural changes to the phenothiazine scaffold. For example, chlorpromazine treatment of psychosis is related to its interaction with dopaminergic receptors. On the other hand, antagonistic action of such drugs on cholinergic receptor systems would be counter-productive for treatment of Alzheimer's disease. In a search for phenothiazines that are inhibitors of cholinesterases, especially butyrylcholinesterase, with potential to treat Alzheimer's disease, we wished to ascertain that such molecules could be devoid of neurotransmitter receptor interactions. To that end, a number of our synthetic N-10-carbonyl phenothiazine derivatives, with cholinesterase inhibitory activity, were tested for interaction with a variety of neurotransmitter receptor systems. We demonstrate that phenothiazines can be prepared without significant neurotransmitter receptor interactions while retaining high potency as cholinesterase ligands for treatment of Alzheimer's disease. Copyright © 2013 Elsevier Ltd. All rights reserved.

  10. MEASURING CHOLINESTERASE ACTIVITY IN HUMAN STUDIES.

    EPA Science Inventory


    Biomonitoring of organophosphorous and carbamate pesticides has focused primarily on the inhibition of blood cholinesterase. Blood biomonitoring, however, can be invasive, time-consuming, and costly, especially in young children and infants. Therefore, saliva biomonitoring ha...

  11. [Effects of cornel iridoid glycoside on activity of cholinesterases in vitro].

    PubMed

    Chu, Si-Juan; Zhang, Lan; Liu, Gang; Zhou, Wen-Xia; Li, Lin

    2013-05-01

    The purpose of the present study was to investigate the effects of cornel iridoid glycoside (CIG) on the activity of cholinesterases in vitro, and to investigate the mechanism of CIG's treating Alzheimer's disease (AD). The sources of cholinesterases were prepared from human blood cells, rat brain homogenate and human blood plasma, respectively. The biochemical methods were used to detect the activity of acetylcholine esterase (AChE) and butyryl cholinesterase (BuChE) to investigate the influence of CIG on cholinesterases. The results showed that CIG inhibited the activity of AChE of human blood cells and rat brain homogenate, with the 50% inhibition rate (IC50) of 1.6 g . L-1 and 3.3 g . L-1, respectively; and the inhibition of AChE of CIG is reversible. CIG also inhibited the activity of BuChE of human blood plasma, with the IC50 of 2.9 g . L-1. In conclusion, CIG can inhibit the activity of AChE and BuChE in vitro, which may be one of the mechanisms of CIG to treat AD.

  12. [Derivatives of lupinin and epilupinin as ligands of various cholinesterases].

    PubMed

    Basova, N E; Kormilitsyn, B N; Rozengart, E V; Saakov, V S; Suvorov, A A

    2012-01-01

    Literature data have been summarized on interaction of cholinesterases of some mammals and arthropods with a group of isomer derivatives of alkaloid lupini and its epimer epilupinin. As substrates of cholinesterases of several mammals there are studied 8 acetates containing in their molecules the chinolysidin bicycle with different structure of N-alkyl radical, which showed certain elements of specificity of action. For 2 isomer esters that are derivatives of the protonated base of the lupinin and epilupinin structures, differences in their substrate characteristics were revealed. The polyenzyme analysis if anticholinesterase efficiency was performed for 30 organophosphorus inhibitors that are dialkoxyphosphorus derivatives of lupinin and epilupinin; as a result, quite a few peculiarities of their action depending on their structure were revealed. Several tested compounds turned out to act as specific inhibitors of cholinesterases of some mammals and arthropods.

  13. A direct method to visualise the aryl acylamidase activity on cholinesterases in polyacrylamide gels

    PubMed Central

    Jaganathan, Lakshmanan; Boopathy, Rathanam

    2000-01-01

    Background In vertebrates, two types of cholinesterases exist, acetylcholinesterase and butyrylcholinesterase. The function of acetylcholinesterase is to hydrolyse acetylcholine, thereby terminating the neurotransmission at cholinergic synapse, while the precise physiological function of butyrylcholinesterase has not been identified. The presence of cholinesterases in tissues that are not cholinergically innervated indicate that cholinesterases may have functions unrelated to neurotransmission. Furthermore, cholinesterases display a genuine aryl acylamidase activity apart from their predominant acylcholine hydrolase activity. The physiological significance of this aryl acylamidase activity is also not known. The study on the aryl acylamidase has been, in part hampered by the lack of a specific method to visualise this activity. We have developed a method to visualise the aryl acylamidase activity on cholinesterase in polyacrylamide gels. Results The o-nitroaniline liberated from o-nitroacetanilide by the action of aryl acylamidase activity on cholinesterases, in the presence of nitrous acid formed a diazonium compound. This compound gave an azo dye complex with N-(1-napthyl)-ethylenediamine, which appeared as purple bands in polyacrylamide gels. Treating the stained gels with trichloroacetic acid followed by Tris-HCl buffer helped in fixation of the stain in the gels. By using specific inhibitors for acetylcholinesterase and butyrylcholinesterase, respectively, differential staining for the aryl acylamidase activities on butyrylcholinesterase and acetylcholinesterase in a sample containing both these enzymes has been demonstrated. A linear relationship between the intensity of colour developed and activity of the enzyme was obtained. Conclusions A novel method to visualise the aryl acylamidase activity on cholinesterases in polyacrylamide gels has been developed. PMID:11231883

  14. A direct method to visualise the aryl acylamidase activity on cholinesterases in polyacrylamide gels.

    PubMed

    Jaganathan, L; Boopathy, R

    2000-01-01

    In vertebrates, two types of cholinesterases exist, acetylcholinesterase and butyrylcholinesterase. The function of acetylcholinesterase is to hydrolyse acetylcholine, thereby terminating the neurotransmission at cholinergic synapse, while the precise physiological function of butyrylcholinesterase has not been identified. The presence of cholinesterases in tissues that are not cholinergically innervated indicate that cholinesterases may have functions unrelated to neurotransmission. Furthermore, cholinesterases display a genuine aryl acylamidase activity apart from their predominant acylcholine hydrolase activity. The physiological significance of this aryl acylamidase activity is also not known. The study on the aryl acylamidase has been, in part hampered by the lack of a specific method to visualise this activity. We have developed a method to visualise the aryl acylamidase activity on cholinesterase in polyacrylamide gels. The o-nitroaniline liberated from o-nitroacetanilide by the action of aryl acylamidase activity on cholinesterases, in the presence of nitrous acid formed a diazonium compound. This compound gave an azo dye complex with N-(1-napthyl)-ethylenediamine, which appeared as purple bands in polyacrylamide gels. Treating the stained gels with trichloroacetic acid followed by Tris-HCl buffer helped in fixation of the stain in the gels. By using specific inhibitors for acetylcholinesterase and butyrylcholinesterase, respectively, differential staining for the aryl acylamidase activities on butyrylcholinesterase and acetylcholinesterase in a sample containing both these enzymes has been demonstrated. A linear relationship between the intensity of colour developed and activity of the enzyme was obtained. A novel method to visualise the aryl acylamidase activity on cholinesterases in polyacrylamide gels has been developed.

  15. An Evaluation of Blood Cholinesterase Testing Methods for Military Health

    DTIC Science & Technology

    2008-05-01

    activity found that only one device has been validated for ChE testing in the field: the Model 400 Test-mate™ ChE kit by EQM Research, Inc. (Cincinnati...OH). Suggested future modifications to the Model 400 Test-mate™ ChE kit include displaying/recording of acetyl-ChE activity uncorrected for...cholinesterase activity , that are routinely monitored by the Department of Defense (DoD). Within DoD, definitive cholinesterase testing is conducted by

  16. Piezoelectric affinity sensors for cocaine and cholinesterase inhibitors.

    PubMed

    Halámek, Jan; Makower, Alexander; Knösche, Kristina; Skládal, Petr; Scheller, Frieder W

    2005-01-30

    We report here the development of piezoelectric affinity sensors for cocaine and cholinesterase inhibitors based on the formation of affinity complexes between an immobilized cocaine derivative and an anti-cocaine antibody or cholinesterase. For both binding reactions benzoylecgonine-1,8-diamino-3,4-dioxaoctane (BZE-DADOO) was immobilized on the surface of the sensor. For immobilization, pre-conjugated BZE-DADOO with 11-mercaptomonoundecanoic acid (MUA) via 2-(5-norbornen-2,3-dicarboximide)-1,1,3,3-tetramethyluronium-tetrafluoroborate (TNTU) allowed the formation of a chemisorbed monolayer on the piezosensor surface. The detection of cocaine was based on a competitive assay. The change of frequency measured after 300s of the binding reaction was used as the signal. The maximum binding of the antibody resulted in a frequency decrease of 35Hz (with an imprecision 3%, n = 3) while the presence of 100pmoll(-1) cocaine decreased the binding by 11%. The limit of detection was consequently below 100pmoll(-1) for cocaine. The total time of one analysis was 15min. This BZE-DADOO-modified sensor was adapted for the detection of organophosphates. BZE-DADOO - a competitive inhibitor - served as binding element for cholinesterase in a competitive assay.

  17. Association of genetic polymorphisms of telomere binding proteins with cholinesterase activity in omethoate-exposed workers.

    PubMed

    Ding, Mingcui; Yang, Yongli; Duan, Xiaoran; Wang, Sihua; Feng, Xiaolei; Wang, Tuanwei; Wang, Pengpeng; Liu, Suxiang; Li, Lei; Liu, Junling; Tang, Lixia; Niu, Xinhua; Zhang, Yuhong; Li, Guoyu; Yao, Wu; Cui, Liuxin; Wang, Wei

    2018-06-18

    Omethoate, an organophosphorous pesticide, can cause a variety of health effects, especially the decrease of cholinesterase activity. The aim of this study is to explore the association of genetic polymorphisms of telomere binding proteins with cholinesterase activity in omethoate-exposed population. Cholinesterase activities in whole blood, red blood cell and plasma were detected using acetylthiocholine and dithio-bis-(nitrobenzoic acid) method; Genetic Genotyping of POT1 rs1034794, POT1 rs10250202, TERF1 rs3863242 and TERT rs2736098 were performed with PCR-RFLP. The cholinesterase activities of whole blood, red blood cells and plasma in exposure group are significantly lower than that of the control group (P < 0.001). Multivariate analysis indicates that exposure group (b = - 1.016, P < 0.001), agender (b = 0.365, P < 0.001), drinking (b = 0.271, P = 0.004) and TERF1rs3863242 (b = - 0.368, P = 0.016) had an impact on cholinesterase activities. The results suggest that individual carrying AG+GG genotypes in TERF1 gene rs3863242 polymorphism were susceptible to damage in cholinesterase induced by omethoate. Copyright © 2018 Elsevier Inc. All rights reserved.

  18. INFLUENCE OF X-IRRADIATION UPON ACTIVITY OF CHOLINESTERASE IN LIVER AND SERUM. PARTS I-III

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Ioroi, M.

    1960-01-01

    The activity of cholinesterase in the liver, studied in rabbits and rats, was more inhibited when the liver was irradiated by a single x-ray dose than by fractionated doses. With l00, 300, and 600 r of whole-body irradiation, the activity of cholinesterase in the liver was stimulated; meanwhile in serum it was inhibited. With l000 and 2000 r, the activities in both serum and liver were severely inhibited. WWhen the diencephalon and spinal cord were irradiated with fractionated doses (l50 r twice a week), the activity of cholinesterase in both liver and serum showed no appreciable change. When whole-body irradiationmore » (l00 r per day) was given, the activity of cholinesterase in both liver and serum was somewhat stimulated. After liver irradiation (200 r per day; total dose 4000 r) the activity of cholinesterase in both liver and serum was inhibited. In patients who showed high activity of cholinesterase in serum before x-ray therapy, the activity was slightly inhibited after x-ray treatment, and patients who showed low activity before therapy were slightly stimulated after x irradiation. (Abstr. Japan Med., l: No. 13, l96l)« less

  19. 21 CFR 862.3240 - Cholinesterase test system.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... is present at nerve endings and in erythrocytes (red blood cells) but is not present in plasma. Pseudo cholinesterase is present in plasma and liver but is not present in erythrocytes. Measurements...

  20. 21 CFR 862.3240 - Cholinesterase test system.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... is present at nerve endings and in erythrocytes (red blood cells) but is not present in plasma. Pseudo cholinesterase is present in plasma and liver but is not present in erythrocytes. Measurements...

  1. 21 CFR 862.3240 - Cholinesterase test system.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... is present at nerve endings and in erythrocytes (red blood cells) but is not present in plasma. Pseudo cholinesterase is present in plasma and liver but is not present in erythrocytes. Measurements...

  2. 21 CFR 862.3240 - Cholinesterase test system.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... is present at nerve endings and in erythrocytes (red blood cells) but is not present in plasma. Pseudo cholinesterase is present in plasma and liver but is not present in erythrocytes. Measurements...

  3. 21 CFR 862.3240 - Cholinesterase test system.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... is present at nerve endings and in erythrocytes (red blood cells) but is not present in plasma. Pseudo cholinesterase is present in plasma and liver but is not present in erythrocytes. Measurements...

  4. Crystal structure of the extracellular cholinesterase-like domain from neuroligin-2

    PubMed Central

    Koehnke, Jesko; Jin, Xiangshu; Budreck, Elaine C.; Posy, Shoshana; Scheiffele, Peter; Honig, Barry; Shapiro, Lawrence

    2008-01-01

    Neuroligins (NLs) are catalytically inactive members of a family of cholinesterase-like transmembrane proteins that mediate cell adhesion at neuronal synapses. Postsynaptic neuroligins engage in Ca2+-dependent transsynaptic interactions via their extracellular cholinesterase domain with presynaptic neurexins (NRXs). These interactions may be regulated by two short splice insertions (termed A and B) in the NL cholinesterase domain. Here, we present the 3.3-Å crystal structure of the ectodomain from NL2 containing splice insertion A (NL2A). The overall structure of NL2A resembles that of cholinesterases, but several structural features are unique to the NL proteins. First, structural elements surrounding the esterase active-site region differ significantly between active esterases and NL2A. On the opposite surface of the NL2A molecule, the positions of the A and B splice insertions identify a candidate NRX interaction site of the NL protein. Finally, sequence comparisons of NL isoforms allow for mapping the location of residues of previously identified mutations in NL3 and NL4 found in patients with autism spectrum disorders. Overall, the NL2 structure promises to provide a valuable model for dissecting NL isoform- and synapse-specific functions. PMID:18250328

  5. Pharmacokinetics of bambuterol in subjects homozygous for the atypical gene for plasma cholinesterase

    PubMed Central

    Bang, Ulla; Nyberg, Lars; Rosenborg, Johan; Viby-Mogensen, Jørgen

    1998-01-01

    Aims It has been assumed that both plasma cholinesterase (EC 3.1.1.8) and oxidative enzymes are needed for optimum formation of the bronchodilator terbutaline from its biscarbamate prodrug bambuterol. The present study aimed at investigating the fate of bambuterol in subjects with deficient plasma cholinesterase but with normal oxidative (CYP2D6) capability. Methods The pharmacokinetics of bambuterol and terbutaline were studied in four healthy subjects (two men and two women) being homozygous for the atypical gene for plasma cholinesterase. Their oxidative metabolism was apparently good as they were all rapid metabolizers of debrisoquine. Bambuterol hydrochloride 20 mg was given orally once daily for 10 days, and plasma and urine samples were taken for 1.5 days (plasma) and 4.5 days (urine) after administration of the last dose. Results The pharmacokinetic parameters in the present study were grossly similar to those found in a study of bambuterol in subjects with normal plasma cholinesterase activity (N). However, subjects with atypical cholinesterase had a shorter terminal half-life of bambuterol (a measure of uptake rate), 4.8–12.6 h vs 8.3–22.3 h in N, and slightly higher plasma concentrations of bambuterol (average concentrations 1.9–3.7 nmol l−1vs 1.5–3.1 nmol l−1 in N). Peak/trough terbutaline plasma concentrations ratios (2.1–3.2) were somewhat increased, but average plasma concentrations (8.3–14.5 nmol l−1) and terminal half-life (16.5–21.8 h) of terbutaline did not differ. Conclusions In Caucasian populations, one subject out of 2500 is homozygous for the atypical gene for plasma cholinesterase. The atypical enzyme has a much lower affinity for bambuterol than the normal enzyme. Nevertheless, the subjects with atypical cholinesterase were able to produce terbutaline as efficiently as normal subjects. This might be explained by an altered uptake and metabolism in the absence of plasma cholinesterase, or the importance of this enzyme

  6. Does diazinon-sprayed market melon alter cholinesterase activity in healthy consumers? A randomized control trial.

    PubMed

    Nematy, M; Tashakori-Behesti, A; Megarbane, B; Bakaiyan, M; Habibi, M; Afashari, R

    2016-06-01

    Food contributes in measurable body burden of the widely used organophosphate pesticides. We designed a randomized controlled open label trial in Mashhad University Hospital in Iran, to study the possible alterations in cholinesterase activity resulting from consuming market melon known to be exposed to diazinon. Fifty-three young healthy volunteers were recruited. Participants were randomized to consume 250 g per day of organic (N = 22) vs. market melon (N = 31) during fifteen days. The primary outcome was the variation of red blood-cell (RBC) cholinesterase activity between day 15 (after) and day 0 (prior the intervention). The secondary outcome was a variation of the plasma cholinesterase activity between both dates. Baseline RBC [5.21 ± 0.93 vs. 5.53 ± 0.99 IU/mL, mean ± SD] and plasma cholinesterase activities [54.0 ± 8.1 vs. 57.4 ± 8.6%] did not significantly differ between organic and market melon-exposed participants, respectively. RBC [5.86 ± 1.27 vs. 5.11 ± 1.2 IU/mL] and plasma cholinesterase activities [58.7 ± 10.0 vs. 50.5 ± 13.0%] significantly increased in organic melon-exposed vs. market melon-exposed participants (p = 0.002 and p = 0.001, respectively). RBC and plasma cholinesterase activities significantly improved after eating organic instead of market melon during fifteen days. However, the consequences on the health of the observed cholinesterase alterations attributed to diazinon dietary intake remain to be determined.

  7. MEASURING CHOLINESTERASE ACTIVITY IN HUMAN SALIVA

    EPA Science Inventory

    To assess the potential for using saliva in pesticide biomonitoring, the consistency of cholinesterase activity in human saliva collected over time was examined. In this pilot study, saliva was collected from 20 healthy adults once per week for 5 consecutive weeks using 2 differe...

  8. MEASURING CHOLINESTERASE ACTIVITY IN HUMAN SALIVA.

    EPA Science Inventory

    To assess the potential for using saliva in pesticide biomonitoring, the consistency of cholinesterase activity in human saliva collected over time was examined. In this pilot study, saliva was collected from 20 healthy adults once per week for 5 consecutive weeks using 2 differe...

  9. Cholinesterase activity during embryonic development in the blood-feeding bug Triatoma patagonica.

    PubMed

    Visciarelli, E C; Chopa, C Sánchez; Picollo, M I; Ferrero, A A

    2011-09-01

    Triatoma patagonica Del Ponte (Hemiptera: Reduviidae), a vector of Chagas' disease, is widely distributed in Argentina and is found in sylvatic and peridomiciliary ecotopes, as well as occasionally in human dwellings after the chemical control of Triatoma infestans. Anti-cholinesteratic products can be applied in peridomiciliary areas and thus knowledge of cholinesterase activity during embryonic development in this species might contribute further information relevant to effective chemical control. Cholinesterase activity was characterized by reactions to eserine 10(-5) m, to increasing concentrations of substrate and to varying centrifugal speeds. Acetylcholinesterase activity was detected on day 4 and was significant from day 5. A reduction in cholinesterase activity towards acetylthiocholine (ATC) was observed on days 9 and 10 of development. Cholinesterase activity towards ATC and butyrylthiocholine (BTC) in homogenates of eggs was inhibited by eserine 10(-5) m. The shape of the curve indicating levels of inhibition at different concentrations of ATC was typical of acetylcholinesterase. Activity towards BTC did not appear to be inhibited by excess substrate, which parallels the behaviour of butyrylcholinesterases. Cholinesterase activity towards ATC was reduced in supernatant centrifuged at 15 000 g compared with supernatant centrifuged at 1100 g. The cholinesterase system that hydrolyzes mainly ATC seems to belong to the nervous system, as indicated by its behaviour towards the substrates assayed, its greater insolubility and the fact that it evolves parallel to the development of the nervous system. Knowledge of biochemical changes associated with the development and maturation of the nervous system during embryonic development would contribute to the better understanding of anti-cholinesteratic compounds with ovicidal action that might be used in control campaigns against vectors of Chagas' disease. © 2011 The Authors. Medical and Veterinary Entomology

  10. Coumarins as cholinesterase inhibitors: A review.

    PubMed

    de Souza, Luana G; Rennã, Magdalena N; Figueroa-Villar, Jose D

    2016-07-25

    The first report in literature of the isolation of coumarin was in the year 1820. After this report, other papers were published demonstrating the isolation and synthesis of coumarin and analogues. These compounds have been studying along the years for several different pathologies. One of these pathologies was Alzheimer's disease (AD), being the main cause of dementia in the contemporary world. There are two hypotheses to explain the pathogenesis mechanism and disease symptoms, then having the "amyloid hypothesis" and the "cholinergic hypothesis". Some drugs for AD are based on the theory of "cholinergic hypothesis", which objective is to increase the concentration of ACh in the synaptic cleft by the inhibition of cholinesterases. Over the last twenty years, many studies with coumarins compounds were reported as cholinesterases inhibitors. The aim of the present review is to discuss the studies and development of new compounds for AD treatment. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  11. Crystal Structure of the Extracellular Cholinesterase-Like Domain from Neuroligin-2

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Koehnke,J.; Jin, X.; Budreck, E.

    Neuroligins (NLs) are catalytically inactive members of a family of cholinesterase-like transmembrane proteins that mediate cell adhesion at neuronal synapses. Postsynaptic neuroligins engage in Ca2+-dependent transsynaptic interactions via their extracellular cholinesterase domain with presynaptic neurexins (NRXs). These interactions may be regulated by two short splice insertions (termed A and B) in the NL cholinesterase domain. Here, we present the 3.3- Angstroms crystal structure of the ectodomain from NL2 containing splice insertion A (NL2A). The overall structure of NL2A resembles that of cholinesterases, but several structural features are unique to the NL proteins. First, structural elements surrounding the esterase active-site regionmore » differ significantly between active esterases and NL2A. On the opposite surface of the NL2A molecule, the positions of the A and B splice insertions identify a candidate NRX interaction site of the NL protein. Finally, sequence comparisons of NL isoforms allow for mapping the location of residues of previously identified mutations in NL3 and NL4 found in patients with autism spectrum disorders. Overall, the NL2 structure promises to provide a valuable model for dissecting NL isoform- and synapse-specific functions.« less

  12. Inhibition of cholinesterases by fluoride in vitro

    PubMed Central

    Cimasoni, Giorgio

    1966-01-01

    1. Series of colorimetric dynamic assays allowed the study of the inhibition of cholinesterases by F− ions in vitro, by using, as sources of enzyme, whole human blood, human serum, homogenized rat brain and two preparations of red blood cells (human and bovine) whose enzymic purity was ascertained. 2. The first evidence of inhibition of human serum pseudocholinesterase by fluoride was noticed at 15–25μm-fluoride. Ten times as much fluoride was needed to start inhibition of acetylcholinesterase of the red blood cells. 3. The action of fluoride on the enzymic reaction was immediate. The reversibility of the inhibition was shown by dialysis and dilution. 4. Kinetic measurements showed that the inhibition under study was not dependent on the substrate concentration and was of the uncompetitive type, similar to that observed in the presence of a heavy metal (cadmium). 5. The activity of serum cholinesterase did not change in the absence of Mg2+ and Ca2+ ions. Fluoride was shown to inhibit the enzyme in the absence of these ions as well as of phosphate. 6. Fluoride could inhibit cholinesterases in the presence of three different substrates and had no action on the non-enzymic hydrolysis. 7. It is thought that the halide is bound reversibly to the enzyme molecule, with the probable exclusion of the active site, but no firm conclusion could be reached on this point. PMID:6007454

  13. Phosphorylated Derivatives of Alkaloids and Nitrogen-containing Heterocycles — Cholinesterase Inhibitors

    NASA Astrophysics Data System (ADS)

    Sadykov, Abid S.; Dalimov, D. N.; Godovikov, Nikolai N.

    1983-10-01

    The review deals with the synthesis and anticholinesterase activities of phosphorylated derivatives of certain alkaloids and nitrogen-containing heterocycles. It is shown that the conformational properties of the alkaloid and nitrogen-containing heterocycle residues in the composition of the organophosphorus inhibitor (OPI) molecule play an important role in the inhibition of the catalytic activity of cholinesterases. The type of inhibition of cholinesterases also varies as a function of chemical structure. The bibliography includes 45 references.

  14. Cholinesterase depression and its association with pesticide exposure across the agricultural season among Latino farmworkers in North Carolina.

    PubMed

    Quandt, Sara A; Chen, Haiying; Grzywacz, Joseph G; Vallejos, Quirina M; Galvan, Leonardo; Arcury, Thomas A

    2010-05-01

    Farmworkers can be exposed to a wide variety of pesticides. Assessing cholinesterase activity over time can be used to monitor exposure to organophosphorus and carbamate pesticides. The goal of this study was to document patterns and variation in cholinesterase levels across the agricultural season (May-August) among field-workers, and to explore the association of cholinesterase depression with pesticide exposure across the agricultural season. Dried blood samples collected from 231 migrant farmworkers sampled from camps in eastern North Carolina up to four times across a summer agricultural season were analyzed for cholinesterase activity, and urine samples were analyzed for metabolites of organophosphorus and carbamate pesticides. Reductions of >or= 15% from an individual's highest value were identified and considered evidence of meaningful cholinesterase activity depression. The average cholinesterase activity levels were lowest in June, with significantly higher mean values in July and August. When adjusted for age, sex, minutes waited to shower, and days worked in the fields, the number of organophosphorus and carbamate pesticides detected in urine predicted reductions in cholinesterase activity. These data demonstrate that workers are experiencing pesticide exposure. Greater enforcement of existing safety regulations or strengthening of these regulations may be warranted. This study demonstrates that serial measurements of cholinesterase activity across an agricultural season can detect exposure to pesticides among field-workers.

  15. Cholinesterase Depression and Its Association with Pesticide Exposure across the Agricultural Season among Latino Farmworkers in North Carolina

    PubMed Central

    Quandt, Sara A.; Chen, Haiying; Grzywacz, Joseph G.; Vallejos, Quirina M.; Galvan, Leonardo; Arcury, Thomas A.

    2010-01-01

    Background Farmworkers can be exposed to a wide variety of pesticides. Assessing cholinesterase activity over time can be used to monitor exposure to organophosphorus and carbamate pesticides. Objectives The goal of this study was to document patterns and variation in cholinesterase levels across the agricultural season (May–August) among field-workers, and to explore the association of cholinesterase depression with pesticide exposure across the agricultural season. Methods Dried blood samples collected from 231 migrant farmworkers sampled from camps in eastern North Carolina up to four times across a summer agricultural season were analyzed for cholinesterase activity, and urine samples were analyzed for metabolites of organophosphorus and carbamate pesticides. Reductions of ≥ 15% from an individual’s highest value were identified and considered evidence of meaningful cholinesterase activity depression. Results The average cholinesterase activity levels were lowest in June, with significantly higher mean values in July and August. When adjusted for age, sex, minutes waited to shower, and days worked in the fields, the number of organophosphorus and carbamate pesticides detected in urine predicted reductions in cholinesterase activity. Conclusions These data demonstrate that workers are experiencing pesticide exposure. Greater enforcement of existing safety regulations or strengthening of these regulations may be warranted. This study demonstrates that serial measurements of cholinesterase activity across an agricultural season can detect exposure to pesticides among field-workers. PMID:20085857

  16. A comparison of serum cholinesterase methods : II.

    DOT National Transportation Integrated Search

    1972-03-01

    Among aerial applicator personnek, the primary value of the periodic blood cholinesterase (ChE) assays is the detection of pesticide poisoning indicated by a decrease in the enzyme activity since the previous (or pre-season) assay. Comparison of thes...

  17. Interaction of cholinesterase modulators with DNA and their cytotoxic activity.

    PubMed

    Janockova, Jana; Gulasova, Zuzana; Plsikova, Jana; Musilek, Kamil; Kuca, Kamil; Mikes, Jaromir; Culka, Lubomir; Fedorocko, Peter; Kozurkova, Maria

    2014-03-01

    This research was focused on a study of the binding properties of a series of cholinesterase reactivators compounds K075 (1), K027 (2) and inhibitors compounds K524, K009 and 7-MEOTA (3-5) with calf thymus DNA. The nature of the interactions between compounds 1-5 and DNA were studied using spectroscopic techniques (UV-vis, fluorescence spectroscopy and circular dichroism). The binding constants for complexes of cholinesterase modulators with DNA were determined from UV-vis spectroscopic titrations (K=0.5 × 10(4)-8.9 × 10(5)M(-1)). The ability of the prepared analogues to relax topoisomerase I was studied with electrophoretic techniques and it was proved that ligands 4 and 5 inhibited this enzyme at a concentration of 30 μM. The biological activity of the novel compounds was assessed through an examination of changes in cell cycle distribution, mitochondrial membrane potential and cellular viability. Inhibitors 3-5 exhibited a cytotoxic effect on HL-60 (human acute promyelocytic leukaemia) cell culture, demonstrated a tendency to affect mitochondrial physiology and viability, and also forced cells to accumulate in the G1/G0-phase of the cell cycle. The cholinesterase reactivators 1 and 2 were found relatively save from the point of view of DNA binding, whereas cholinesterase inhibitors 3-5 resulted as strong DNA binding agents that limit their plausible use. Copyright © 2013 Elsevier B.V. All rights reserved.

  18. The significance of low substrate concentration measurements for mechanistic interpretation in cholinesterases.

    PubMed

    Stojan, Jure

    2013-03-25

    Cholinesterases do not follow the Michaelis-Menten kinetics. In the past, many reaction schemes were suggested to explain their complex interactions during the substrate turnover. Covalent catalysis was recognized very early and therefore, double intermediate traditional reaction scheme for the hydrolysis of good substrates at low concentrations was postulated. However, at intermediate and high substrate concentrations homotropic pseudocooperative effects take place in all cholinesterases, due to the nature of their buried active center. In this study, the significance and usefulness of experimental data obtained at low substrate concentrations, where only one substrate molecule accesses the active site at a time, are to be specified for the overall mechanistic evaluations. Indeed, different interpretations are expected when data are processed with equations derived from different reaction schemes. Consequently, the scheme with two substrate binding sites which comprises the structurally evidenced fully occupied active site as ultimate cause for substantially decreased cholinesterase activity at extremely high substrate concentrations is considered here. A special emphasis is put on butyrylcholinesterase, the enzyme with the largest active site among cholinesterases, where the pseudocooperative effects appear at much higher concentrations than in acetylcholinesterases. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  19. Cholinesterase inhibitors modify the activity of intrinsic cardiac neurons.

    PubMed

    Darvesh, Sultan; Arora, Rakesh C; Martin, Earl; Magee, David; Hopkins, David A; Armour, J Andrew

    2004-08-01

    Cholinesterase inhibitors used to treat the symptoms of Alzheimer's disease (AD) inhibit both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), albeit to different degrees. Because central and peripheral neurons, including intrinsic cardiac neurons located on the surface of the mammalian heart, express both BuChE and AChE, we studied spontaneously active intrinsic cardiac neurons in the pig as a model to assess the effects of inhibition of AChE compared to BuChE. Neuroanatomical experiments showed that some porcine intrinsic cardiac neurons expressed AChE and/or BuChE. Enzyme kinetic experiments with cholinesterase inhibitors, namely, donepezil, galantamine, (+/-) huperzine A, metrifonate, rivastigmine, and tetrahydroaminoacridine, demonstrated that these compounds differentially inhibited porcine AChE and BuChE. Donepezil and (+/-) huperzine A were better reversible inhibitors of AChE, and galantamine equally inhibited both the enzymes. Tetrahydroaminoacridine was a better reversible inhibitor of BuChE. Rivastigmine caused more rapid inactivation of BuChE as compared to AChE. Neurophysiological studies showed that acetylcholine and butyrylcholine increase or decrease the spontaneous activity of the intrinsic cardiac neurons. Donepezil, galantamine, (+/-) huperzine A, and tetrahydroaminoacridine changed spontaneous neuronal activity by about 30-35 impulses per minute, while rivastigmine changed it by approximately 100 impulses per minute. It is concluded that (i) inhibition of AChE and BuChE directly affects the porcine intrinsic cardiac nervous system, (ii) the intrinsic cardiac nervous system represents a suitable model for examining the effects of cholinesterase inhibitors on mammalian neurons in vivo, and (iii) the activity of intrinsic cardiac neurons may be affected by pharmacological agents that inhibit cholinesterases.

  20. Protease inhibitors and indoleamines selectively inhibit cholinesterases in the histopathologic structures of Alzheimer disease.

    PubMed Central

    Wright, C I; Guela, C; Mesulam, M M

    1993-01-01

    Neurofibrillary tangles and amyloid plaques express acetylcholinesterase and butyrylcholinesterase activity in Alzheimer disease. We previously reported that traditional acetylcholinesterase inhibitors such as BW284C51, tacrine, and physostigmine were more potent inhibitors of the acetylcholinesterase in normal axons and cell bodies than of the acetylcholinesterase in plaques and tangles. We now report that the reverse pattern is seen with indoleamines (such as serotonin and its precursor 5-hydroxytryptophan), carboxypeptidase inhibitor, and the nonspecific protease inhibitor bacitracin. These substances are more potent inhibitors of the cholinesterases in plaques and tangles than of those in normal axons and cell bodies. These results show that the enzymatic properties of plaque and tangle-associated cholinesterases diverge from those of normal axons and cell bodies. The selective susceptibility to bacitracin and carboxypeptidase inhibitor indicates that the catalytic sites of plaque and tangle-bound cholinesterases are more closely associated with peptidase or protease-like properties than the catalytic sites of cholinesterases in normal axons and cell bodies. This shift in enzymatic affinity may lead to the abnormal protein processing that is thought to play a major role in the pathogenesis of Alzheimer disease. The availability of pharmacological and dietary means for altering brain indoleamines raises therapeutic possibilities for inhibiting the abnormal cholinesterase activity associated with Alzheimer disease. Images PMID:8421706

  1. DIFFERENTIAL PROFILES OF CHOLINESTERASE INHIBITION AND NEUROBEHAVIORAL EFFECTS IN RATS EXPOSED TO FENSMIPHOS OR PROFENOPHOS.

    EPA Science Inventory

    This manuscript examines the relationship between cholinesterase inhibition and behavioral effects produced by two pesticides, fenamiphos and profenophos. Both pesticides greatly inhibit blood cholinesterase but the brain is relatively spared up to lethal doses. Despite the sim...

  2. Longitudinal Assessment of Blood Cholinesterase Activities Over 2 Consecutive Years Among Latino Nonfarmworkers and Pesticide-Exposed Farmworkers in North Carolina.

    PubMed

    Quandt, Sara A; Pope, Carey N; Chen, Haiying; Summers, Phillip; Arcury, Thomas A

    2015-08-01

    This study (1) describes patterns of whole blood total cholinesterase, acetylcholinesterase, and butyrylcholinesterase activities across the agricultural season, comparing farmworkers and nonfarmworkers; and (2) explores differences between farmworkers' and non-farmworkers' likelihood of cholinesterase depression. Blood samples from 210 Latino male farmworkers and 163 Latino workers with no occupational pesticide exposure collected 8 times across 2 agricultural seasons were analyzed. Mean cholinesterase activity levels and depressions 15% or more were compared by month. Farmworkers had significantly lower total cholinesterase and butyrylcholinesterase activities in July and August and lower acetylcholinesterase activity in August. Farmworkers had significantly greater likelihood of cholinesterase depression for each cholinesterase measure across the agricultural season. A repeated-measures design across 2 years with a nonexposed control group demonstrated anticholinesterase effects in farmworkers. Current regulations designed to prevent pesticide exposure are not effective.

  3. Cholinesterase inhibitors for rarer dementias associated with neurological conditions.

    PubMed

    Li, Ying; Hai, Shan; Zhou, Yan; Dong, Bi Rong

    2015-03-03

    Rarer dementias include Huntington's disease (HD), cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), frontotemporal dementia (FTD), dementia in multiple sclerosis (MS) and progressive supranuclear palsy (PSP). Cholinesterase inhibitors, including donepezil, galantamine and rivastigmine, are considered to be the first-line medicines for Alzheimer's disease and some other dementias, such as dementia in Parkinson's disease. Cholinesterase inhibitors are hypothesised to work by inhibiting the enzyme acetylcholinesterase (AChE) which breaks down the neurotransmitter acetylcholine. Cholinesterase inhibitors may also lead to clinical improvement for rarer dementias associated with neurological conditions. To assess the efficacy and safety of cholinesterase inhibitors for cognitive impairment or dementia associated with neurological conditions. We searched the Cochrane Dementia and Cognitive Improvement Group's Specialised Register, CENTRAL, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS, several trial registries and grey literature sources in August 2013. We included randomised, double-blind, controlled trials assessing the efficacy of treatment of rarer dementias associated with neurological conditions with currently marketed cholinesterase inhibitors. Two review authors independently assessed eligibility and quality of trials, and extracted data. We used the standard methodological procedures of the Cochrane Collaboration. We included eight RCTs involving 567 participants. Six studies used a simple parallel-group design; the other two consisted of an open-label treatment period followed by a randomised phase. All trials were well concealed for allocation and double-blind, however the sample sizes of most trials were small. All trials used placebo as control. We performed meta-analyses for some outcomes in patients with MS. For all other conditions, results are presented narratively.Two trials included patients with HD; one

  4. Advances toward multifunctional cholinesterase and β-amyloid aggregation inhibitors.

    PubMed

    Panek, Dawid; Wichur, Tomasz; Godyń, Justyna; Pasieka, Anna; Malawska, Barbara

    2017-10-01

    The emergence of a multitarget design approach in the development of new potential anti-Alzheimer's disease agents has resulted in the discovery of many multifunctional compounds focusing on various targets. Among them the largest group comprises inhibitors of both cholinesterases, with additional anti-β-amyloid aggregation activity. This review describes recent advances in this research area and presents the most interesting compounds reported over a 2-year span (2015-2016). The majority of hybrids possess heterodimeric structures obtained by linking structurally active fragments interacting with different targets. Multipotent cholinesterase inhibitors with β-amyloid antiaggregating activity may additionally possess antioxidative, neuroprotective or metal-chelating properties or less common features such as anti-β-secretase or τ-antiaggregation activity.

  5. The kinetics of inhibition of erythrocyte cholinesterase by monomethylcarbamates

    PubMed Central

    Reiner, E.; Simeon-Rudolf, V.

    1966-01-01

    1. The kinetics of the interaction of erythrocyte cholinesterase with 1-naphthyl N-methylcarbamate, 2-isopropoxyphenyl N-methylcarbamate and phenyl N-methylcarbamate were studied. Rate constants for inhibition and rate constants for spontaneous reactivation were determined. The calculated rate constants for spontaneous reactivation agreed well with those obtained experimentally. 2. The degree of inhibition obtained after preincubation of enzyme and inhibitor was found to be independent of both the substrate concentration and the dilution of the inhibited enzyme. 3. The reaction between the enzyme and the inhibitor was consistent with carbamates being regarded as poor substrates of cholinesterases. There was no evidence for the formation of a reversible complex between the enzyme and the carbamate. PMID:5941343

  6. Resistance in cholinesterase activity after an acute and subchronic exposure to azinphos-methyl in the freshwater gastropod Biomphalaria straminea.

    PubMed

    Bianco, Karina; Otero, Sofía; Oliver, Agustina Balazote; Nahabedian, Daniel; Kristoff, Gisela

    2014-11-01

    Organophosphorous and carbamates insecticides are ones of the most popular classes of pesticides used in agriculture. Its success relies on their high acute toxicity and rapid environmental degradation. These insecticides inhibit cholinesterase and cause severe effects on aquatic non-target species, particularly in invertebrates. Since the properties of cholinesterases may differ between species, it is necessary to characterize them before their use as biomarkers. Also organophosphorous and carbamates inhibit carboxylesterases and the use of both enzymes for biomonitoring is suggested. Azinphos-methyl is an organophosphorous insecticide used in several parts of the word. In Argentina, it is the most applied insecticide in fruit production in the north Patagonian region. It was detected with the highest frequency in superficial and groundwater of the region. This work aims to evaluate the sensitivity of B. straminea cholinesterases and carboxylesterases to the OP azinphos-methyl including estimations of 48 h NOEC and IC50 of the pesticide and subchronic effects at environmentally relevant concentrations. These will allow us to evaluate the possibility of using cholinesterase and carboxylesterase of B. straminea as sensitive biomarkers. Previously a partial characterization of these enzymes will be performed. As in most invertebrates, acetylthiocholine was the preferred hydrolyzed substrate of B. straminea ChE, followed by propionylthiocholine and being butyrylthiocholine hydrolysis very low. Cholinesterase activity of B. straminea was significantly inhibited by the selective cholinesterases inhibitor (eserine) and by the selective inhibitor of mammalian acethylcholinesterase (BW284c51). In contrast, iso-OMPA, a specific inhibitor of butyrylcholinesterase, did not inhibit cholinesterase activity. These results suggest that cholinesterase activity in total soft tissue of B. straminea corresponds to acethylcholinesterase. Carboxylesterases activity was one order of

  7. Syntheses, cholinesterases inhibition, and molecular docking studies of pyrido[2,3-b]pyrazine derivatives.

    PubMed

    Hameed, Abdul; Zehra, Syeda T; Shah, Syed J A; Khan, Khalid M; Alharthy, Rima D; Furtmann, Norbert; Bajorath, Jürgen; Tahir, Muhammad N; Iqbal, Jamshed

    2015-11-01

    Cholinesterases, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), have a role in cholinergic deficit which evidently leads to Alzheimer's disease (AD). Inhibition of cholinesterases with small molecules is an attractive strategy in AD therapy. This study demonstrates synthesis of pyrido[2,3-b]pyrazines (6a-6q) series, their inhibitory activities against both cholinesterases, AChE and BChE, and molecular docking studies. The bioactivities data of pyrido[2,3-b]pyrazines showed 3-(3'-nitrophenyl)pyrido[2,3-b]pyrazine 6n a potent dual inhibitor among the series against both AChE and BChE with IC50 values of 0.466 ± 0.121 and 1.89 ± 0.05 μm, respectively. The analogues 3-(3'-methylphenyl)pyrido[2,3-b]pyrazine 6c and 3-(3'-fluorophenyl)pyrido[2,3-b]pyrazine 6f were found to be selective inhibition for BChE with IC50 values of 0.583 ± 0.052 μm and AChE with IC50 value of 0.899 ± 0.10 μm, respectively. Molecular docking studies of the active compounds suggested the putative binding modes with cholinesterases. The potent compounds among the series could potentially serves as good leads for the development of new cholinesterase inhibitors. © 2015 John Wiley & Sons A/S.

  8. From Split to Sibenik: The Tortuous Pathway in the Cholinesterase Field

    PubMed Central

    Taylor, Palmer

    2010-01-01

    The interim between the first and tenth International Cholinesterase meetings has seen remarkable advances associated with the applications of structural biology and recombinant DNA methodology to our field. The cloning of the cholinesterase genes led to the identification of a new super family of proteins, termed the α,β–hydrolase fold; members of this family possess a four helix bundle capable of linking structural subunits to the functioning globular protein. Sequence comparisons and three dimensional structural studies revealed unexpected cousins possessing this fold that, in turn, revealed three distinct functions for the α,β-hydrolase proteins. These encompass: (1) a capacity for hydrolytic cleavage of a great variety of substrates, (2) a heterophilic adhesion function that results in trans-synaptic associations in linked neurons, (3) a chaperone function leading to stabilization of nascent protein and its trafficking to an extracellular or secretory storage location. The analysis and modification of structure may go beyond understanding mechanism, since it may be possible to convert the cholinesterases to efficient detoxifying agents of organophosphatases assisted by added oximes. Also, the study of the relationship between the α,β–hydrolase fold proteins and their biosynthesis may yield means by which aberrant trafficking may be corrected, enhancing expression of mutant proteins. Those engaged in cholinesterase research should take great pride in our accomplishments punctuated by the series of ten meetings. The momentum established and initial studies with related proteins all hold great promise for the future. PMID:20493179

  9. Tracking the origin and divergence of cholinesterases and neuroligins: the evolution of synaptic proteins.

    PubMed

    Lenfant, Nicolas; Hotelier, Thierry; Bourne, Yves; Marchot, Pascale; Chatonnet, Arnaud

    2014-07-01

    A cholinesterase activity can be found in all kingdoms of living organism, yet cholinesterases involved in cholinergic transmission appeared only recently in the animal phylum. Among various proteins homologous to cholinesterases, one finds neuroligins. These proteins, with an altered catalytic triad and no known hydrolytic activity, display well-identified cell adhesion properties. The availability of complete genomes of a few metazoans provides opportunities to evaluate when these two protein families emerged during evolution. In bilaterian animals, acetylcholinesterase co-localizes with proteins of cholinergic synapses while neuroligins co-localize and may interact with proteins of excitatory glutamatergic or inhibitory GABAergic/glycinergic synapses. To compare evolution of the cholinesterases and neuroligins with other proteins involved in the architecture and functioning of synapses, we devised a method to search for orthologs of these partners in genomes of model organisms representing distinct stages of metazoan evolution. Our data point to a progressive recruitment of synaptic components during evolution. This finding may shed light on the common or divergent developmental regulation events involved into the setting and maintenance of the cholinergic versus glutamatergic and GABAergic/glycinergic synapses.

  10. OHOLO Conference (36th): Multidisciplinary Approaches to Cholinesterase Functions Held in Eilat, Israel on April 6 - 10, 1992.

    DTIC Science & Technology

    1992-04-10

    Acetylcholinesterase in Mosquitoes. Short oral presentation A23.- Roshchina, V.V. - Plant Cholinesterases. A24.- Seidman Shlomo, Revital Ben-Aziz Aloya, Yael ...Hermona Soreq - Differential Transcriptional Control of Cholinesterase Genes in Developing Megakaryocytes. Short oral presentation B13.- Loewenstein Yael ...Against Organophos- phate Poisoning. B20.- Richter ED., I. Orun, J. Ronen , WQ Lu, Y. Yodfat, F. Grauer, J. Marzouk, M. Gordon - Cholinesterase Revisited

  11. Regional cholinesterase activity in white-throated sparrow brain is differentially affected by acephate (Orthene®)

    USGS Publications Warehouse

    Vyas, N.B.; Kuenzel, W.J.; Hill, E.F.; Romo, G.A.; Komaragiri, M.V.S.

    1996-01-01

    Effects of a 14-day dietary exposure to an organophosphorus pesticide, acephate (acetylphosphoramidothioic acid O,S-dimethyl ester), were determined on cholinesterase activity in three regions (basal ganglia, hippocampus, and hypothalamus) of the white-throated sparrow, Zonotrichia albicollis, brain. All three regions experienced depressed cholinesterase activity between 0.5–2 ppm acephate. The regions exhibited cholinesterase recovery at 2–16 ppm acephate; however, cholinesterase activity dropped and showed no recovery at higher dietary levels (>16 ppm acephate). Evidence indicates that the recovery is initiated by the magnitude of depression, not the duration. In general, as acephate concentration increased, differences in ChE activity among brain regions decreased. Three terms are introduced to describe ChE response to acephate exposure: 1) ChE resistance threshold, 2) ChE compensation threshold, and 3) ChE depression threshold. It is hypothesized that adverse effects to birds in the field may occur at pesticide exposure levels customarily considered negligible.

  12. Experience with a cholinesterase histochemical technique for rectal suction biopsies in the diagnosis of Hirschsprung's disease

    PubMed Central

    Trigg, P. H.; Belin, R.; Haberkorn, S.; Long, W. J.; Nixon, H. H.; Plaschkes, J.; Spitz, L.; Willital, G. H.

    1974-01-01

    Cryostat sections from 160 rectal suction biopsies were stained for cholinesterases by the method of Karnovsky and Roots (1964) in an attempt to facilitate the diagnosis of Hirschsprung's disease. The method proved at least as reliable as experienced assessment of paraffin haematoxylin-eosin sections, and appeared to offer the advantages of reduced scanning fatigue and superior demonstration of the increased cholinesterase-positive nerves in Hirschprung's disease. Contrary to the findings of Meier-Ruge (1971) it was not possible to base a diagnosis on mucosal cholinesterase activity. Images PMID:4832300

  13. Longitudinal Assessment of Blood Cholinesterase Activities over Two Consecutive Years among Latino Non-farmworkers and Pesticide-Exposed Farmworkers in North Carolina

    PubMed Central

    Quandt, Sara A; Pope, Carey N.; Chen, Haiying; Summers, Phillip; Arcury, Thomas A.

    2015-01-01

    Objective This study (1) describes patterns of whole blood total cholinesterase, acetylcholinesterase, and butyrylcholinesterase activities across the agricultural season, comparing farmworkers and non-farmworkers; and (2) explores differences between farmworkers' and non-farmworkers' likelihood of cholinesterase depression. Methods Blood samples from 210 Latino male farmworkers and 163 Latino workers with no occupational pesticide exposure collected eight times across two agricultural seasons were analyzed. Mean cholinesterase activity levels and depressions ≥15% were compared by month. Results Farmworkers had significantly lower total cholinesterase and butyrylcholinesterase activities in July and August and lower acetylcholinesterase activity in August. Farmworkers had significantly greater likelihood of cholinesterase depression for each cholinesterase measure across the agricultural season. Significance A repeated-measures design across two years with a non-exposed control group demonstrated anticholinesterase effects in farmworkers. Current regulations designed to prevent pesticide exposure are not effective. PMID:26247638

  14. Evaluation of Candidate Genes for Cholinesterase Activity in Farmworkers Exposed to Organophosphorus Pesticides: Association of Single Nucleotide Polymorphisms in BCHE

    PubMed Central

    Howard, Timothy D.; Hsu, Fang-Chi; Grzywacz, Joseph G.; Chen, Haiying; Quandt, Sara A.; Vallejos, Quirina M.; Whalley, Lara E.; Cui, Wei; Padilla, Stephanie; Arcury, Thomas A.

    2010-01-01

    Background Organophosphate pesticides act as cholinesterase inhibitors. For those with agricultural exposure to these chemicals, risk of potential exposure-related health effects may be modified by genetic variability in cholinesterase metabolism. Cholinesterase activity is a useful, indirect measurement of pesticide exposure, especially in high-risk individuals such as farmworkers. To understand fully the links between pesticide exposure and potential human disease, analyses must be able to consider genetic variability in pesticide metabolism. Objectives We studied participants in the Community Participatory Approach to Measuring Farmworker Pesticide Exposure (PACE3) study to determine whether cholinesterase levels are associated with single-nucleotide polymorphisms (SNPs) involved in pesticide metabolism. Methods Cholinesterase levels were measured from blood samples taken from 287 PACE3 participants at up to four time points during the 2007 growing season. We performed association tests of cholinesterase levels and 256 SNPs in 30 candidate genes potentially involved in pesticide metabolism. A false discovery rate (FDR) p-value was used to account for multiple testing. Results Thirty-five SNPs were associated (unadjusted p < 0.05) based on at least one of the genetic models tested (general, additive, dominant, and recessive). The strongest evidence of association with cholinesterase levels was observed with two SNPs, rs2668207 and rs2048493, in the butyrylcholinesterase (BCHE) gene (FDR adjusted p = 0.15 for both; unadjusted p = 0.00098 and 0.00068, respectively). In participants with at least one minor allele, cholinesterase levels were lower by 4.3–9.5% at all time points, consistent with an effect that is independent of pesticide exposure. Conclusions Common genetic variation in the BCHE gene may contribute to subtle changes in cholinesterase levels. PMID:20529763

  15. Methylmercury-cholinesterase interactions in rats.

    PubMed Central

    Hastings, F L; Lucier, G W; Klein, R

    1975-01-01

    The interaction of methylmercury hydroxide (MMH) and cholinesterases was studied in male and female rats. MMH administered subcutaneously in doses of 10 mg/kg for 2 days reduced the level of plasma cholinesterase (ButChE) by 68% in females and 47% in males while brain acetylcholinesterase (AChE) was unaffected. Normal females had higher but more variable ButChE levels than normal males. In a time-course experiment, a single dose of MMH (10 mg/kg) reduced ButChE levels when mercury levels reached 22 mug/ml in the blood. A 10% reduction in brain AChE was observed at 72 hours; however, mercury reached a concentration of only 2.0 mug/g in brain tissue. The determination of the Michaelis constant Km and maximum velocity value Vmax for butyrylcholine and ButChE in control and MMH-treated (1 mg/kg) animals indicated that MMH reduced Vmax only. Since no loss in ButChE activity occurred when MMH and control plasma were incubated in vitro, MMH is not a direct inhibitor of ButChE. Because only the inactive monomeric form of ButChE contains free sulfhydryl groups, it is postulated that MMH combines covalently with the sulfur, preventing formation of active enzyme. By analogy, it is believed this is also the case with AChE. PMID:1227853

  16. Anti-cholinesterase activity of the standardized extract of Syzygium aromaticum L.

    PubMed

    Dalai, Manoj K; Bhadra, Santanu; Chaudhary, Sushil K; Bandyopadhyay, Arun; Mukherjee, Pulok K

    2014-04-01

    Clove (Syzygium aromaticum) is a well-known culinary spice with strong aroma; contains a high amount of oil known as clove oil. The major phyto-constituent of the clove oil is eugenol. Clove and its oil possess various medicinal uses in indigenous medicine as an antiseptic, anti-oxidant, analgesic and neuroprotective properties. Thus, it draws much attention among researchers from pharmaceutical, food and cosmetic industries. The aim of the present study was to determine the anti-cholinesterase activity of the methanol extract of clove, its oil and eugenol. In vitro anti-cholinesterase activity of S. aromaticum was performed by a thin layer chromatography bio autography, 96 well micro titer plate and kinetic methods. Reverse phase high performance liquid chromatography (RP-HPLC) analysis was carried out to identify the biomarker compound eugenol in clove oil. Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition study revealed that eugenol possess better inhibition of the enzymes than extract and oil. Clove extract, its oil and eugenol showed better inhibition of AChE than BChE. Polyphenolic compound eugenol was detected through RP-HPLC analysis. The content of eugenol in essential oil was found to be 0.5 μg/ml. Kinetic analysis of the cholinesterase inhibition study of the extract; clove oil and eugenol have shown that they possess mixed type of inhibition for AChE and non-competitive type of inhibition for BChE. These results might be useful in explaining the effect of clove as anti-cholinesterase agent for the management of cognitive ailments like Alzheimer's disease.

  17. Dual inhibitors of cholinesterases and monoamine oxidases for Alzheimer's disease.

    PubMed

    Knez, Damijan; Sova, Matej; Košak, Urban; Gobec, Stanislav

    2017-05-01

    Accumulating evidence indicates a solid relationship between several enzymes and Alzheimer's disease. Cholinesterases and monoamine oxidases are closely associated with the disease symptomatology and progression and have been tackled simultaneously using several multifunctional ligands. This design strategy offers great chances to alter the course of Alzheimer's disease, in addition to alleviation of the symptoms. More than 15 years of research has led to the identification of various dual cholinesterase/monoamine oxidase inhibitors, while some showing positive outcomes in clinical trials, thus giving rise to additional research efforts in the field. The aim of this review is to provide an update on the novel dual inhibitors identified recently and to shed light on their therapeutic potential.

  18. Identification of the structural mutation responsible for the dibucaine-resistant (atypical) variant form of human serum cholinesterase

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    McGuire, M.C.; Nogueira, C.P.; Bartels, C.F.

    1989-02-01

    A point mutation in the gene for human serum cholinesterase was identified that changes Asp-70 to Gly in the atypical form of serum cholinesterase. The mutation in nucleotide 209, which changes codon 70 from GAT to GGT, was found by sequencing a genomic clone and sequencing selected regions of DNA amplified by the polymerase chain reaction. The entire coding sequences for usual and atypical cholinesterases were compared, and no other consistent base differences were found. The nucleotide-209 mutation was detected in all five atypical cholinesterase families examined. There was complete concordance between this mutation and serum cholinesterase phenotypes for allmore » 14 heterozygous and 6 homozygous atypical subjects tested. The mutation causes the loss of a Sau3A1 restriction site; the resulting DNA fragment length polymorphism was verified by electrophoresis of {sup 32}P-labeled DNA restriction fragments from usual and atypical subjects. Dot-blot hybridization analysis with a 19-mer allele-specific probe to the DNA amplified by the polymerase chain reaction distinguished between the usual and atypical genotypes. The authors conclude that the Asp-70 {yields} Gly mutation accounts for reduced affinity of atypical cholinesterase for choline esters and that Asp-70 must be an important component of the anionic site. Heterogeneity in atypical alleles may exist, but the Asp-70 point mutation may represent an appreciable portion of the atypical gene pool.« less

  19. Reactions of Methamidophos with Mammalian Cholinesterase,

    DTIC Science & Technology

    1978-07-01

    dynamics of its reactions with insmvnstlian cholinesterase (CbE), Methamidophos is highly toxic to the cosmon housefly , Muaca domestics L., exhibiting a...between two properties which tend to oppose each other. It does not react rapidly with housefly —head ChE. However , the enzyme—inhibitor complex...toxicity of methamidophos to female houseflies was reported (Quistad et al., 1970) to be approximately the same as that of other potent

  20. Chronic Neuropsychological Sequelae of Cholinesterase Inhibitors in the Absence of Structural Brain Damage: Two Cases of Acute Poisoning

    PubMed Central

    Roldán-Tapia, Lola; Leyva, Antonia; Laynez, Francisco; Santed, Fernando Sánchez

    2005-01-01

    Here we describe two cases of carbamate poisoning. Patients AMF and PVM were accidentally poisoned by cholinesterase inhibitors. The medical diagnosis in both cases was overcholinergic syndrome, as demonstrated by exposure to cholinesterase inhibitors. The widespread use of cholinesterase inhibitors, especially as pesticides, produces a great number of human poisoning events annually. The main known neurotoxic effect of these substances is cholinesterase inhibition, which causes cholinergic overstimulation. Once AMF and PVM had recovered from acute intoxication, they were subjected to extensive neuropsychological evaluation 3 and 12 months after the poisoning event. These assessments point to a cognitive deficit in attention, memory, perceptual, and motor domains 3 months after intoxication. One year later these sequelae remained, even though the brain magnetic resonance imaging (MRI) and computed tomography (CT) scans were interpreted as being within normal limits. We present these cases as examples of neuropsychological profiles of long-term sequelae related to acute poisoning by cholinesterase inhibitor pesticides and show the usefulness of neuropsychological assessment in detecting central nervous system dysfunction in the absence of biochemical or structural markers. PMID:15929901

  1. Isothiocyanates: cholinesterase inhibiting, antioxidant, and anti-inflammatory activity.

    PubMed

    Burčul, Franko; Generalić Mekinić, Ivana; Radan, Mila; Rollin, Patrick; Blažević, Ivica

    2018-12-01

    Finding a new type of cholinesterase inhibitor that would overcome the brain availability and pharmacokinetic parameters or hepatotoxic liability has been a focus of investigations dealing with the treatment of Alzheimer's disease. Isothiocyanates have not been previously investigated as potential cholinesterase inhibitors. These compounds can be naturally produced from their glucosinolate precursors, secondary metabolites widely distributed in our daily Brassica vegetables. Among 11 tested compounds, phenyl isothiocyanate and its derivatives showed the most promising inhibitory activity. 2-Methoxyphenyl ITC showed best inhibition on acetylcholinesterase with IC 50 of 0.57 mM, while 3-methoxyphenyl ITC showed the best inhibition on butyrylcholinesterase having 49.2% at 1.14 mM. Assessment of the antioxidant efficacy using different methods led to a similar conclusion. The anti-inflammatory activity was also tested using human COX-2 enzyme, ranking phenyl isothiocyanate, and 3-methoxyphenyl isothiocyanate as most active, with ∼99% inhibition at 50 μM.

  2. Assessment of exposure to organophosphate insecticides during spraying in Haiti: monitoring of urinary metabolites and blood cholinesterase levels*

    PubMed Central

    Warren, McWilson; Spencer, Harrison C.; Churchill, Frederick C.; Francois, Velly Jean; Hippolyte, Robert; Staiger, Michael A.

    1985-01-01

    Measurement of blood cholinesterase activity and of the urinary metabolites of fenitrothion (p-nitrocresol) and malathion (monocarboxylic acid) was used to assess the exposure to these insecticides of workers in the Haitian malaria control programme and of residents in the sprayed houses. Cholinesterase activity was significantly reduced at the end of the working week in 3 out of 28 fenitrothion workers. Urinary levels of p-nitrocresol (PNC) in the spraymen ranged from 2.2 to 25.2 mg/l. In fenitrothion workers who had no direct contact with spraying (weighers and supervisors), the cholinesterase activity remained ≥ 75% of the normal control value, and the urinary PNC levels were relatively low. Urinary malathion monocarboxylic acid (MCA) levels at the end of the working week ranged between 1.1 and 5.3 mg/l in workers using malathion and their blood cholinesterase activity remained essentially normal. In both groups of workers the cholinesterase levels improved and the urinary excretion of metabolites decreased after 2 days of rest from the spraying operations. In the residents of the sprayed houses, low concentrations of PNC and MCA were detected in the urine 1 day after spraying and measurable but reduced levels were still present after 7 days. In all these cases the cholinesterase activity remained ≥ 75% of the normal control value. PMID:3874716

  3. THE LOCALIZATION OF CHOLINESTERASE ACTIVITY IN RAT CARDIAC MUSCLE BY ELECTRON MICROSCOPY

    PubMed Central

    Karnovsky, Morris J.

    1964-01-01

    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

  4. The history of cholinesterase reactivation: hydroxylamine and pyridinium aldoximes.

    PubMed

    Petroianu, G A

    2012-10-01

    Hydroxylamine (NH2OH) the substance which will turn out to be of importance to those interested in the treatment of organophosporus cholinesterase inhibitor exposure, was synthesized by Wilhem Clemens Lossen in 1865 while working in Halle as an assistant in the laboratory of Wilhelm Heinrich Heintz. The Lossen synthesis generated hydroxylamine in aqueous solution. Anhydrous hydroxylamine was prepared almost simultaneously by Lobry de Bruyn and Crismer (1891). Using hydroxylamine as a starting point Meyer synthesized aldoximes and ketoximes (1897). Lange, a PhD student of Ladenburg, isolated 2-methyl-pyridine (alpha-picoline). Some fifty years later Wilson, working in the laboratory of Nachmansohn, demonstrated the ability of hydroxylamine to reactivate cholinesterase inhibited by organophosphates. Finally Wilson and Ginsburg using 2-methyl-pyridine as a starting point synthesized the first pyridinium aldoxime reactivator of clinical relevance, pralidoxime (1955).

  5. NEURO-GUMORALE SUBSTANCES OF DOG BLOOD DURING ACUTE RADIATION SICKNESS. I. CHANGES IN BLOOD ACETYLCHOLINE AND CHOLINESTERASE SYSTEM (in Russian)

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Kuznetzova, N.E.

    1963-01-01

    Experiments carried out on 13 male dogs, 2 to 5 years old and weighing 10 to 20 kg, showed that in the initial stages of chroric radiation sickness the blood content of acetylcholine increased and the cholinesterase decreased. Moreove r, the increase in the acetylcholine level during the first 3 to 4 hrs proceeded at a greater rate than the cholinesterase decrease. Shifts in the enzyme system were more pronounced in dogs with greater resistance. However, during the recovery period acetylcholine and cholinesterase restoration took place at earlier periods in dogs with higher resistance. Not only was the cholinesterase activitymore » restored, but it increased to 1.5 to 2 times the initial level. The level of acetylcholine and cholinesterase was not restored in the blood of dogs during terminal periods. In dogs exposed to subacute doses, 300 r, enzyme normalization took place 29 to 41 days following exposure. Correlation of data on enzyme changes in single and chronic exposures indicated identical trends It was postulated that acetylcholine -cholinesterase participate in compensating reactions of organisms during radiation sickness. (R.V.J.)« less

  6. Serum and Plasma Cholinesterase Activity in the Cape Griffon Vulture (Gyps coprotheres).

    PubMed

    Naidoo, Vinny; Wolter, Kerri

    2016-04-28

    Vulture (Accipitridae) poisonings are a concern in South Africa, with hundreds of birds dying annually. Although some of these poisonings are accidental, there has been an increase in the number of intentional baiting of poached rhinoceros (Rhinocerotidae) and elephant (Elephantidae) carcasses to kill vultures that alert officials to poaching sites by circling overhead. The primary chemicals implicated are the organophosphorous and carbamate compounds. Although most poisoning events can be identified by dead vultures surrounding the scavenged carcass, weak birds are occasionally found and brought to rehabilitation centers for treatment. The treating veterinarian needs to make an informed decision on the cause of illness or poisoning prior to treatment. We established the reference interval for serum and plasma cholinesterase activity in the Cape Griffon Vulture ( Gyps coprotheres ) as 591.58-1,528.26 U/L, providing a clinical assay for determining potential exposure to cholinesterase-depressing pesticides. Both manual and automated samplers were used with the butyrylthiocholine method. Species reference intervals for both serum and plasma cholinesterase showed good correlation and manual and automated measurements yielded similar results.

  7. Current Pyridostigmine Bromide and Huperzine A Studies and Future Cholinesterase Screening Using the WRAIR Whole Blood Cholinesterase Assay

    DTIC Science & Technology

    2004-11-15

    1 CURRENT PYRIDOSTIGMINE BROMIDE AND HUPERZINE A STUDIES AND FUTURE CHOLINESTERASE SCREENING USING THE WRAIR WHOLE BLOOD...selective (e.g. Huperzine A ) and non-selective (carbamate) inhibitors (e.g. pyridostigmine bromide, PB). We found that volunteers given pyridostigmine...profile of healthy elderly volunteers receiving Huperzine A . 52.7 ± 1.5% inhibition was observed at the end of an increasing dose regimen (final dose

  8. Identification of the structural mutation responsible for the dibucaine-resistant (atypical) variant form of human serum cholinesterase.

    PubMed Central

    McGuire, M C; Nogueira, C P; Bartels, C F; Lightstone, H; Hajra, A; Van der Spek, A F; Lockridge, O; La Du, B N

    1989-01-01

    A point mutation in the gene for human serum cholinesterase was identified that changes Asp-70 to Gly in the atypical form of serum cholinesterase. The mutation in nucleotide 209, which changes codon 70 from GAT to GGT, was found by sequencing a genomic clone and sequencing selected regions of DNA amplified by the polymerase chain reaction. The entire coding sequences for usual and atypical cholinesterases were compared, and no other consistent base differences were found. A polymorphic site near the C terminus of the coded region was detected, but neither allele at this locus segregated consistently with the atypical trait. The nucleotide-209 mutation was detected in all five atypical cholinesterase families examined. There was complete concordance between this mutation and serum cholinesterase phenotypes for all 14 heterozygous and 6 homozygous atypical subjects tested. The mutation causes the loss of a Sau3A1 restriction site; the resulting DNA fragment length polymorphism was verified by electrophoresis of 32P-labeled DNA restriction fragments from usual and atypical subjects. Dot-blot hybridization analysis with a 19-mer allele-specific probe to the DNA amplified by the polymerase chain reaction distinguished between the usual and atypical genotypes. We conclude that the Asp-70----Gly mutation (acidic to neutral amino acid substitution) accounts for reduced affinity of atypical cholinesterase for choline esters and that Asp-70 must be an important component of the anionic site. Heterogeneity in atypical alleles may exist, but the Asp-70 point mutation may represent an appreciable portion of the atypical gene pool. Images PMID:2915989

  9. Activity and determinants of cholinesterases and paraoxonase-1 in blood of workers exposed to non-cholinesterase inhibiting pesticides.

    PubMed

    Lozano-Paniagua, David; Gómez-Martín, Antonio; Gil, Fernando; Parrón, Tesifón; Alarcón, Raquel; Requena, Mar; Lacasaña, Marina; Hernández, Antonio F

    2016-11-25

    Pesticide exposure has been associated with different adverse health effects which may be modulated to some extent by paraoxonase-1 (PON1) activity and genetic polymorphisms. This study assessed seasonal variations in PON1 activity (using paraoxon -POase-, phenylacetate -AREase-, diazoxon -DZOase- and dihydrocoumarin -DHCase- as substrates), erythrocyte acetylcholinesterase (AChE) and plasma cholinesterase (using butyrylthiocholine -BuChE- and benzoylcholine -BeChE- as substrates. The study population consisted of intensive agriculture workers regularly exposed to pesticides other than organophosphates and non-exposed controls from Almería (Southeastern Spain). The effect of common genetic polymorphisms of PON1 and BCHE on paraoxonase-1 and cholinesterase activities toward different substrates was also assessed. Linear mixed models were used to compare esterase activities in agricultural workers and control subjects over the two study periods (high and low exposure to pesticides). The significant decrease in AChE and increase in BuChE and BeChE activities observed in workers with respect to control subjects was attributed to pesticide exposure. Workers also had higher levels of AREase, DZOase and, to a lesser extent, of POase, but showed decreased DHCase activity. While PON1 Q192R and PON1 -108C/T gene polymorphisms were significantly associated with all PON1 activities, PON1 L55M showed a significant association with AREase, DZOase and DHCase. BCHE-K (Karlow variant) was significantly associated with lower BeChE activity (but not with BuChE) and BCHE-A (atypical variant) showed no significant association with any cholinesterase activity. These findings suggest that increased PON1, BuChE and BeChE activities in exposed workers might result from an adaptive response against pesticide exposure to compensate for adverse effects at the biochemical level. This response appears to be modulated by PON1 and BCHE gene polymorphisms. Copyright © 2016 Elsevier Ireland Ltd

  10. Evaluation of Candidate Genes for cholinesterase Activity in Farmworkers Exposed to organophosphorous Pesticides-Association of SNPs in BCHE

    EPA Science Inventory

    Background: Organophosphate pesticides act as cholinesterase inhibitors, and as such may give rise to potential neurological effects. Cholinesterase activity is a useful, indirect measurement of pesticide exposure, especially in high-risk individuals such as farmworkers. To und...

  11. Synthesis and Preliminary Evaluation of Phenyl 4-123I-Iodophenylcarbamate for Visualization of Cholinesterases Associated with Alzheimer Disease Pathology.

    PubMed

    Macdonald, Ian R; Reid, G Andrew; Pottie, Ian R; Martin, Earl; Darvesh, Sultan

    2016-02-01

    Acetylcholinesterase and butyrylcholinesterase accumulate with brain β-amyloid (Aβ) plaques in Alzheimer disease (AD). The overall activity of acetylcholinesterase is found to decline in AD, whereas butyrylcholinesterase has been found to either increase or remain the same. Although some cognitively normal older adults also have Aβ plaques within the brain, cholinesterase-associated plaques are generally less abundant in such individuals. Thus, brain imaging of cholinesterase activity associated with Aβ plaques has the potential to distinguish AD from cognitively normal older adults, with or without Aβ accumulation, during life. Current Aβ imaging agents are not able to provide this distinction. To address this unmet need, synthesis and evaluation of a cholinesterase-binding ligand, phenyl 4-(123)I-iodophenylcarbamate ((123)I-PIP), is described. Phenyl 4-iodophenylcarbamate was synthesized and evaluated for binding potency toward acetylcholinesterase and butyrylcholinesterase using enzyme kinetic analysis. This compound was subsequently rapidly radiolabeled with (123)I and purified by high-performance liquid chromatography. Autoradiographic analyses were performed with (123)I-PIP using postmortem orbitofrontal cortex from cognitively normal and AD human brains. Comparisons were made with an Aβ imaging agent, 2-(4'-dimethylaminophenyl)-6-(123)I-iodo-imidazo[1,2-a]pyridine ((123)I-IMPY), in adjacent brain sections. Tissues were also stained for Aβ and cholinesterase activity to visualize Aβ plaque load for comparison with radioligand uptake. Synthesized and purified PIP exhibited binding to cholinesterases. (123)I was successfully incorporated into this ligand. (123)I-PIP autoradiography with human tissue revealed accumulation of radioactivity only in AD brain tissues in which Aβ plaques had cholinesterase activity. (123)I-IMPY accumulated in brain tissues with Aβ plaques from both AD and cognitively normal individuals. Radiolabeled ligands specific for

  12. A review on cholinesterase inhibitors for Alzheimer's disease.

    PubMed

    Anand, Preet; Singh, Baldev

    2013-04-01

    Alzheimer's disease (AD), a progressive neurodegenerative disorder, is characterized by the deficits in the cholinergic system and deposition of beta amyloid (Aβ) in the form of neurofibrillary tangles and amyloid plaques. Since the cholinergic system plays an important role in the regulation of learning and memory processes, it has been targetted for the design of anti-Alzheimer's drugs. Cholinesterase inhibitors enhance cholinergic transmission directly by inhibiting the enzyme acetylcholinesterase (AChE) which hydrolyses acetylcholine. Furthermore, it has been also demonstrated that both acetylcholinesterase and butrylcholinesterase (BuChE) play an important role in Aβ-aggregation during the early stages of senile plaque formation. Therefore, AChE and BuChE inhibition have been documented as critical targets for the effective management of AD by an increase in the availability of acetylcholine in the brain regions and decrease in the Aβ deposition. This review discusses the different classes of cholinesterase inhibitors including tacrine, donepezil, rivastigmine, galantamine, xanthostigmine, para-aminobenzoic acid, coumarin, flavonoid, and pyrrolo-isoxazole analogues developed for the treatment of AD.

  13. Localization of cholinesterases in the chicken nervous system and the problem of the selective neurotoxicity of organophosphorus compounds

    PubMed Central

    Cavanagh, J. B.; Holland, P.

    1961-01-01

    Using the thiocholine method, a restricted survey has been made of cholinesterases in the spinal cord and brain stem of the chicken. No simple relation between sites of selective damage in organophosphorus neurotoxicity and centres of cholinesterase activity could be adduced. Moreover, no significant differences between species susceptible and insusceptible to poisoning by these compounds were found by this method. It is concluded that, while cholinesterase may well play an intermediary role in the intoxication, other factors determine the selective damage to certain neurones and their processes. ImagesFig. 1Fig. 2Fig. 3Fig. 4Fig. 5Fig. 6 PMID:13691740

  14. Absence of neurovisual effects due to tissue and blood cholinesterase depression in a chronic disulfoton feeding study in dogs.

    PubMed

    Jones, R D; Hastings, T F; Landes, A M

    1999-06-01

    Technical grade disulfoton (DiSyston) was fed to Beagle dogs (four animals per sex and treatment level) at nominal concentrations of 0, 0.5, 4 and 12 ppm for 1 year. The purpose of this study was to characterize the potential general and neurovisual toxicity according to routine Environmental Protection Agency (EPA) guideline requirements, and by use of ancillary ocular and neurologic tests established in this Laboratory. Ophthalmological tests included: ocular tissue cholinesterase and histopathology, electroretinography (ERG), tracking, refractivity, intraocular pressure and pachymetry (corneal thickness) measurements. Neurological examinations included; peripheral and cranial reflex tests, task performance tests, gait and behavioral observations, and rectal temperature measurements. Plasma, erythrocyte and corneal cholinesterase were significantly depressed at 4 and 12 ppm in both sexes. Brain cholinesterase was depressed at 4 and 12 ppm in females. Retinal cholinesterase was depressed at 4 ppm in females and at 12 ppm in males. Ciliary body cholinesterase was depressed at 12 ppm in both sexes. Despite these cholinergic effects, there were no ophthalmologic findings in measurements of ERG, tracking, refractivity, intraocular pressure or pachymetry. There were no clinical neurology findings related to compound administration. We conclude that 0.5 ppm was a no-observable effect level (NOEL), and effects were limited to cholinesterase changes that had no detectable physiologic impact. This study demonstrates that special mechanistic investigations incorporated within guideline studies, enhances scientific integrity and can minimize the need for dedicated organ system studies.

  15. Structural insights into cholinesterases inhibition by harmane β-carbolinium derivatives: a kinetics-molecular modeling approach.

    PubMed

    Torres, Juliana M; Lira, Aline F; Silva, Daniel R; Guzzo, Lucas M; Sant'Anna, Carlos M R; Kümmerle, Arthur E; Rumjanek, Victor M

    2012-09-01

    The natural indole alkaloids, the β-carbolines, are often associated with cholinesterase inhibition, especially their quaternary salts, which frequently have higher activity than the free bases. Due to lack of information explaining this fact in the literature, the cholinesterase inhibition by the natural product harmane and its two β-carbolinium synthetic derivative salts (N-methyl and N-ethyl) was explored, together with a combination of kinetics and a molecular modeling approach. The results, mainly for the β-carbolinium salts, demonstrated a noncompetitive inhibition profile, ruling out previous findings which associated cholinesterase inhibition by β-carbolinium salts to a possible mimicking of the choline moiety of the natural substrate, acetylcholine. Molecular modeling studies corroborate this kind of inhibition through analyses of inhibitor/enzyme and inhibitor/substrate/enzyme complexes of both enzymes. Copyright © 2012 Elsevier Ltd. All rights reserved.

  16. Cholinesterase inhibitory triterpenoids from the bark of Garcinia hombroniana.

    PubMed

    Jamila, Nargis; Khairuddean, Melati; Yeong, Khaw Kooi; Osman, Hasnah; Murugaiyah, Vikneswaran

    2015-02-01

    Context: Garcinia hombroniana Pierre, known as manggis hutan in Malaysia is a rich source of xanthones and benzophenones. This study was aimed to isolate and characterize potential cholinesterase inhibitors from the extracts of G. hombroniana bark and investigate their interactions with the enzymes. The dichloromethane extract afforded five triterpenoids which were characterized by NMR and mass spectral techniques. Cholinesterase inhibitory assay and molecular docking were performed to get insight of the inhibitory activity and molecular interactions of the compounds. The compounds were also tested for their antioxidant capacity. The isolated triterpenoids were identified as: 2β-hydroxy-3α-O-caffeoyltaraxar-14-en-28-oic acid (1), taraxerol (2), taraxerone (3), betulin (4) and betulinic acid (5). Compound 1 was the most active dual inhibitor of both AChE and BChE. Compound 1 also showed good antioxidant activities. Compound 1 had dual and moderate inhibitory activity on AChE and BChE worthy for further investigations.

  17. Cholinesterase inhibitors for patients with Alzheimer's disease: systematic review of randomised clinical trials

    PubMed Central

    Kaduszkiewicz, Hanna; Zimmermann, Thomas; Beck-Bornholdt, Hans-Peter; van den Bussche, Hendrik

    2005-01-01

    Objectives Pharmacological treatment of Alzheimer's disease focuses on correcting the cholinergic deficiency in the central nervous system with cholinesterase inhibitors. Three cholinesterase inhibitors are currently recommended: donepezil, rivastigmine, and galantamine. This review assessed the scientific evidence for the recommendation of these agents. Data sources The terms “donepezil”, “rivastigmine”, and “galantamine”, limited by “randomized-controlled-trials” were searched in Medline (1989-November 2004), Embase (1989-November 2004), and the Cochrane Database of Systematic Reviews without restriction for language. Study selection All published, double blind, randomised controlled trials examining efficacy on the basis of clinical outcomes, in which treatment with donepezil, rivastigmine, or galantamine was compared with placebo in patients with Alzheimer's disease, were included. Each study was assessed independently, following a predefined checklist of criteria of methodological quality. Results 22 trials met the inclusion criteria. Follow-up ranged from six weeks to three years. 12 of 14 studies measuring the cognitive outcome by means of the 70 point Alzheimer's disease assessment scale—cognitive subscale showed differences ranging from 1.5 points to 3.9 points in favour of the respective cholinesterase inhibitors. Benefits were also reported from all 12 trials that used the clinician's interview based impression of change scale with input from caregivers. Methodological assessment of all studies found considerable flaws—for example, multiple testing without correction for multiplicity or exclusion of patients after randomisation. Conclusion Because of flawed methods and small clinical benefits, the scientific basis for recommendations of cholinesterase inhibitors for the treatment of Alzheimer's disease is questionable. PMID:16081444

  18. Surface-Electrochemical Sensor for the Measurement of Anti-Cholinesterase Activity

    NASA Astrophysics Data System (ADS)

    Matsuura, Hiroaki; Sato, Yukari; Yabuki, Soichi; Sawaguchi, Takahiro; Mizutani, Fumio

    An organophosphorus pesticide, ethylthiometon (0.01-0.2 ppm) was determined by using a surface-electrochemical sensor system: the monolayer formation (chemisorption)-reductive desorption of thiocholine was applied to monitor the activity change of cholinesterase caused by the pesticide.

  19. "Nonspecific" cholinesterase and acetylcholinesterase in rat tissues: molecular forms, structural and catalytic properties, and significance of the two enzyme systems.

    PubMed Central

    Vigny, M; Gisiger, V; Massoulié, J

    1978-01-01

    "Nonspecific" cholinesterase (acylcholine acylhydrolase; EC 3.1.1.8) from various rat tissues has been found to exist in several stable molecular forms that appear as exact counterparts of molecular forms of acetylcholinesterase (acetylcholine hydrolase; EC 3.1.1.7). The sedimentation pattern of cholinesterase was similar to that of acetylcholinesterase with a small but significant shift between the sedimentation coefficients of the corresponding forms. Extraction yields in different media also demonstrated a close parallelism between the two enzyme systems. Other properties, such as thermal stability and catalytic characteristics, indicated both differences and similarities. In spite of the structural resemblance implied by their physicochemical properties, cholinesterase did not crossreact with antibodies against acetylcholinesterase. The nature of the relationships revealed by these studies and their bearing on the physiological significance of cholinesterases are discussed. PMID:78492

  20. Molecular modeling and biological evaluation of 2-N,N-dimethylaminecyclohexyl 1-N‧,N‧-dimethylcarbamate isomers and their methylsulfate salts as cholinesterases inhibitors

    NASA Astrophysics Data System (ADS)

    Bocca, Cleverson C.; Rittner, Roberto; Höehr, Nelci F.; Pinheiro, Glaucia M. S.; Abiko, Layara A.; Basso, Ernani A.

    2010-11-01

    This work presents a detailed theoretical and experimental study on the inhibitory properties of 2- N,N-dimethylaminecyclohexyl 1- N',N'-dimethylcarbamate isomers and their methylsulfate salts against the cholinesterases enzymes. The in vitro inhibition test performed by the Ellman's method showed that the salt form compounds were more active than the neutral ones in cholinesterases inhibition. The trans salt showed good selectivity towards the inhibition of erythrocyte cholinesterase with a maximum limit around 90% and 55% for the plasma cholinesterase inhibition. Molecular modeling, docking and experimental results performed in this study showed to be important initial steps toward the development of a novel pharmaceuticals in the fight against Alzheimer's disease.

  1. Cholinesterase characterization of two autochthonous species of Ria de Aveiro (Diopatra neapolitana and Solen marginatus) and comparison of sensitivities towards a series of common contaminants.

    PubMed

    Nunes, Bruno; Resende, Sara Teixeira

    2017-05-01

    Biomonitoring of chemical contamination requires the use of well-established and validated tools, including biochemical markers that can be potentially affected by exposure to important environmental toxicants. Cholinesterases (ChEs) are present in a large number of species and have been successfully used for decades to discriminate the environmental presence of specific groups of pollutants. The success of cholinesterase inhibition has been due to their usefulness as a biomarker to address the presence of organophosphate (OP) and carbamate (CB) pesticides. However, its use in ecotoxicology has not been limited to such chemicals, and several other putative classes of contaminants have been implicated in cholinesterasic impairment. Nevertheless, the use of cholinesterases as a monitoring tool requires its full characterization in species to be used as test organisms. This study analyzed and differentiated the various cholinesterase forms present in two autochthonous organisms from the Ria de Aveiro (Portugal) area, namely the polychaete Diopatra neapolitana and the bivalve Solen marginatus, to be used in subsequent monitoring studies. In addition, this study also validated the putative use of the now characterized cholinesterasic forms by analyzing the in vitro effects of common anthropogenic contaminants, such as detergents, pesticides, and metals. The predominant cholinesterasic form found in tissues of D. neapolitana was acetylcholinesterase, while homogenates of S. marginatus were shown to possess an atypical cholinesterasic form, with a marked preference for propionylthiocholine. Cholinesterases from D. neapolitana were generally non-responsive towards the majority of the selected chemicals. On the contrary, strong inhibitory effects were reported for ChEs of S. marginatus following exposure to the selected pesticides.

  2. Japanese quail acute exposure to methamidophos: experimental design, lethal, sub-lethal effects and cholinesterase biochemical and histochemical expression.

    PubMed

    Foudoulakis, Manousos; Balaskas, Christos; Csato, Attila; Szentes, Csaba; Arapis, Gerassimos

    2013-04-15

    We exposed the Japanese quail (Coturnix coturnix japonica) to the organophosphate methamidophos using acute oral test. Mortality and sub-lethal effects were recorded in accordance to internationally accepted protocols. In addition cholinesterases were biochemically estimated in tissues of the quail: brain, liver and plasma. Furthermore, brain, liver and duodenum cryostat sections were processed for cholinesterase histochemistry using various substrates and inhibitors. Mortalities occurred mainly in the first 1-2h following application. Sub-lethal effects, such as ataxia, ruffled feathers, tremor, salivation and reduced or no reaction to external stimuli were observed. Biochemical analysis in the brain, liver and plasma indicates a strong cholinesterase dependent inhibition with respect to mortality and sub-lethal effects of the quail. The histochemical staining also indicated a strong cholinesterase inhibition in the organs examined and the analysis of the stained sections allowed for an estimation and interpretation of the intoxication effects of methamidophos, in combination with tissue morphology visible by Haematoxylin and Eosin staining. We conclude that the use of biochemistry and histochemistry for the biomarker cholinesterase, may constitute a significantly novel approach for understanding the results obtained by the acute oral test employed in order to assess the effects of methamidophos and other chemicals known to inhibit this very important nervous system enzyme. Copyright © 2012 Elsevier B.V. All rights reserved.

  3. Studies on the storage stability of human blood cholinesterases : I.

    DOT National Transportation Integrated Search

    1970-01-01

    Whole blood, red cell, and plasma preparations were stored at room temperature, refrigerated, and frozen. Samples were assayed over a 50-day period using the technique of constant-pH titration (pH-Stat). At least 90% of the cholinesterase activity in...

  4. A microfluorometric assay for cholinesterases, suitable for multiple kinetic determinations of picomoles of released thiocholine.

    PubMed

    Parvari, R; Pecht, I; Soreq, H

    1983-09-01

    A highly sensitive microfluorometric assay for cholinesterases has been developed. Enzymatic activity is measured by monitoring the thiocholine produced by specific hydrolysis of acetylthiocholine. This is carried out by reacting the thiocholine formed with the fluorogenic compound N-(4(7 diethylamino-4-methylcoumarin-3-yl)phenyl)maleimide to yield an intensely fluorescent product. The assay is linear over a range extending from a few picomoles to nanomoles of thiocholine. The specificity and accuracy of this microfluorometric assay were examined using microgram quantities of rat brain tissue as a source for cholinesterases. The specific activities and the Km values determined by this new method for both cholinesterase activities present in the brain (acetylcholine hydrolase, EC 3.1.1.7, and "nonspecific" cholinesterase-acylcholine acylhydrolase, EC 3.1.1.8) were identical to those reported earlier using the less sensitive spectrophotometric and radiometric methods. The background emission caused by nonenzymatic hydrolysis of the substrate is relatively low, and does not exceed background values encountered in other methods. The assay may be used for monitoring the kinetics of enzymatic activities in microscale reaction mixtures, providing a linear determination of the thiocholine produced over a period of at least 30 h at room temperature. The method can also be adapted for use in other enzymatic assays where reagents containing thiol groups can be produced or consumed.

  5. [How aliphatic alcohols and ph affect reactional capability of the horse blood serum cholinesterase at its interaction with organophosphorus inhibitors].

    PubMed

    Basova, N E; Kormilitsin, B N; Perchenok, A Iu; Rozengart, E V; Saakov, V S; Suvorov, A A

    2013-01-01

    There was studied action of aliphatic alcohols (ethanol, propanol, isopropanol, n-butanol, isobutanol, secbutanol, tretbetanol) and pH on various kinds of reactional capability the serum cholinesterase. At the alcohols-affected inhibition of the cholinesterase hydrolytic activity, the determining role was played not the total number carbon atoms in the alcohol molecule, but by the "effective length" of the carbohydrate chain. The fact that the presence of alcohols did not affect parameters of the reverse cholinesterase inhibition with onium ions tetramethylammonium and choline allows suggesting the absence of effect solvents on specific acetylcholine sorption in the enzyme active center. With aid of two rows of hydrophobic organophosphorus inhibitors (OPI), we have managed to estimate both the degree and the character itself of the modifying action of alcohols and pH on the process of irreversible inhibition of serum cholinesterase.

  6. Nature as a source of metabolites with cholinesterase-inhibitory activity: an approach to Alzheimer's disease treatment.

    PubMed

    Pinho, Brígida R; Ferreres, Federico; Valentão, Patrícia; Andrade, Paula B

    2013-12-01

    Alzheimer's disease (AD) is the most common cause of dementia, being responsible for high healthcare costs and familial hardships. Despite the efforts of researchers, no treatment able to delay or stop AD progress exists. Currently, the available treatments are only symptomatic, cholinesterase inhibitors being the most widely used drugs. Here we describe several natural compounds with anticholinesterase (acetylcholinesterase and butyrylcholinesterase) activity and also some synthetic compounds whose structures are based on those of natural compounds. Galantamine and rivastigmine are two cholinesterase inhibitors used in therapeutics: galantamine is a natural alkaloid that was extracted for the first time from Galanthus nivalis L., while rivastigmine is a synthetic alkaloid, the structure of which is modelled on that of natural physostigmine. Alkaloids include a high number of compounds with anticholinesterases activity at the submicromolar range. Quinones and stilbenes are less well studied regarding cholinesterase inhibition, although some of them, such as sargaquinoic acid or (+)-α-viniferin, show promising activity. Among flavonoids, flavones and isoflavones are the most potent compounds. Xanthones and monoterpenes are generally weak cholinesterase inhibitors. Nature is an almost endless source of bioactive compounds. Several natural compounds have anticholinesterase activity and others can be used as leader compounds for the synthesis of new drugs. © 2013 Royal Pharmaceutical Society.

  7. TLC-bioautographic evaluation of in vitro anti-tyrosinase and anti-cholinesterase potentials of sandalwood oil.

    PubMed

    Misra, Biswapriya B; Dey, Satyahari

    2013-02-01

    Sandalwood oil, rich in sesquiterpenoid alcohols, has been used in traditional medicinal systems as a relaxant and coolant. Besides, sandalwood oil is used as an ingredient in numerous skin fairness enhancing cosmetics. However, there is no available information on biological activities that relate to the above applications. Hence, the anti-tyrosinase and anti-cholinesterase potentials of sandalwood oil were probed by both TLC-bioautographic and colorimetric methods. Results obtained from colorimetric assays indicated that sandalwood oil is a potent inhibitor of tyrosinase (IC50 = 171 microg mL(-1)) and cholinesterases (IC50 = 4.8-58 microg mL(-1)), in comparison with the positive controls used in the assays, kojic acid and physostigmine, respectively. The TLC-bioautographic assays indicated that alpha-santalol, the major constituent of the oil, is a strong inhibitor of both tyrosinase and cholinesterase. These in vitro results indicate that there is a great potential of this essential oil for use in the treatment of Alzheimer's disease, as well as in skin-care.

  8. Synthesis and bioevaluation of new tacrine-cinnamic acid hybrids as cholinesterase inhibitors against Alzheimer's disease.

    PubMed

    Chen, Yao; Zhu, Jie; Mo, Jun; Yang, Hongyu; Jiang, Xueyang; Lin, Hongzhi; Gu, Kai; Pei, Yuqiong; Wu, Liang; Tan, Renxiang; Hou, Jing; Chen, Jingyi; Lv, Yang; Bian, Yaoyao; Sun, Haopeng

    2018-12-01

    Small molecule cholinesterases inhibitor (ChEI) provides an effective therapeutic strategy to treat Alzheimer's disease (AD). Currently, the discovery of new ChEI with multi-target effect is still of great importance. Herein, we report the synthesis, structure-activity relationship study and biological evaluation of a series of tacrine-cinnamic acid hybrids as new ChEIs. All target compounds are evaluated for their in vitro cholinesterase inhibitory activities. The representatives which show potent activity on cholinesterase, are evaluated for the amyloid β-protein self-aggregation inhibition and in vivo assays. The optimal compound 19, 27, and 30 (human AChE IC 50  = 10.2 ± 1.2, 16.5 ± 1.7, and 15.3 ± 1.8 nM, respectively) show good performance in ameliorating the scopolamine-induced cognition impairment and preliminary safety in hepatotoxicity evaluation. These compounds deserve further evaluation for the development of new therapeutic agents against AD.

  9. Resorcinol-, catechol- and saligenin-based bronchodilating β2-agonists as inhibitors of human cholinesterase activity.

    PubMed

    Bosak, Anita; Knežević, Anamarija; Gazić Smilović, Ivana; Šinko, Goran; Kovarik, Zrinka

    2017-12-01

    We investigated the influence of bronchodilating β2-agonists on the activity of human acetylcholinesterase (AChE) and usual, atypical and fluoride-resistant butyrylcholinesterase (BChE). We determined the inhibition potency of racemate and enantiomers of fenoterol as a resorcinol derivative, isoetharine and epinephrine as catechol derivatives and salbutamol and salmeterol as saligenin derivatives. All of the tested compounds reversibly inhibited cholinesterases with K i constants ranging from 9.4 μM to 6.4 mM and had the highest inhibition potency towards usual BChE, but generally none of the cholinesterases displayed any stereoselectivity. Kinetic and docking results revealed that the inhibition potency of the studied compounds could be related to the size of the hydroxyaminoethyl chain on the benzene ring. The additional π-π interaction of salmeterol's benzene ring and Trp286 and hydrogen bond with His447 probably enhanced inhibition by salmeterol which was singled out as the most potent inhibitor of all the cholinesterases.

  10. Relationship Between Brain and Plasma Carbaryl Levels and Cholinesterase Inhibition

    EPA Science Inventory

    Carbaryl is a N-methylcarbamate pesticide and, like others in this class, is a reversible inhibitor of cholinesterase (ChE) enzymes. Although studied for many years, there is a surprising lack of information relating tissue levels of carbaryl with ChE activity in the same animals...

  11. Biological Evaluation of Azomethine-dihydroquinazolinone Conjugates as Cancer and Cholinesterase Inhibitors.

    PubMed

    Iqbal, Jamshed; Saeed, Aamer; Shah, Syed J A; al-Rashida, Mariya; Shams-ul Mahmood

    2016-01-01

    In an attempt to discover novel anti-cancer agents and potent cholinesterase inhibitors, 11 azomethine-dihydroquinazolinone conjugates were evaluated against lung carcinoma cells and cholinesterases. Most of the compounds exhibited significant cytotoxicity at low micromolar concentrations and were less toxic to normal cells. After 24 h incubation period, 2i showed maximum cytotoxicity. The 4-bromine substituted compounds showed higher acetylcholinesterase (AChE) inhibitory activity than other screened compounds. The most active compound 2c, among the series, had an IC50 value 209.8 µM against AChE. The tested compounds showed less inhibition against butyrylcholinesterase. Molecular docking studies were performed in order to investigate the plausible binding modes of synthesized compounds. The compounds can be further optimized to treat cancer and Alzheimer's disease. These derivatives may open new pathways for introducing new therapies for curing cancer and senile dementia.

  12. Cholinesterase inhibitory effects of Rhizophora lamarckii, Avicennia officinalis, Sesuvium portulacastrum and Suaeda monica: Mangroves inhabiting an Indian coastal area (Vellar Estuary).

    PubMed

    Suganthy, Natarajan; Pandian, Shanmugiahthevar Karutha; Devi, Kasi Pandima

    2009-06-01

    Alzheimer's disease is a progressive neurodegenerative illness accounting for approximately 50% of all types of dementia in elderly people. The only symptomatic treatment proven effective to date is the use of cholinesterase inhibitors to augment surviving cholinergic activity. The purpose of this study is to investigate cholinesterase inhibitory activity of mangroves as an alternative medicine for the treatment of Alzheimer's disease. About nine mangrove plants, which were used as folk medicine in tropical countries, were collected from Parangipettai, Vellar estuary, Tamilnadu, India. Nile Tilapia muscle homogenate was used as source of enzyme. Inhibitory effect of methanolic leaf extract was assessed under in vitro condition by incubating various concentration of the extract with total cholinesterase and butyryl cholinesterase and assessing their residual activities by Ellman's colorimetric method. The results showed that of the nine plants screened Rhizophora lamarckii, Suaeda monica, Avicennia officinalis and Sesuvium portulacastrum showed 50% inhibitory activity to both TChE and BChE at concentrations less than 2 mg/mL when compared to other plant extracts, which was comparable to the standard drug Donepezil. Phytochemical analysis showed the presence of alkaloids in high concentration which might be correlated to its cholinesterase inhibitory activity.

  13. Chemical constituents and their acetyl cholinesterase inhibitory and antioxidant activities from leaves of Acanthopanax henryi: potential complementary source against Alzheimer's disease.

    PubMed

    Zhang, Xiao Dan; Liu, Xiang Qian; Kim, Yang Hee; Whang, Wan Kyunn

    2014-05-01

    The aim of this study was to investigate chemical constituents of the leaves of Acanthopanax henryi, and their antioxidant, acetyl cholinesterase inhibitory activities. Caffeoyl quinic acid derivates and flavonoids were obtained from A. henry, through column chromatography technologies, and the content of major constituents was determined by the HPLC-UV method. Anti-oxidant activity of the isolated metabolites was evaluated by free radical scavenging (DPPH, ABTS radicals) and superoxide anion scavenging. The results showed that di-caffeoyl quinic acid derivates had stronger antioxidant activity than positive controls (ascorbic acid, trolox and allopurinol). Acetyl cholinesterase inhibitory activity was estimated on the constituents, among which, quercetin, 4-caffeoyl-quinic acid and 4,5-caffeoyl quinic acid were found to have strong acetyl cholinesterase inhibitory activity with IC50 values ranging from 62.6 to 121.9 μM. The present study showed that some of the tested constituents from the leaves of A. henryi exhibit strong antioxidant and acetyl cholinesterase inhibitory effects. This suggest that the leaves of A. henryi can be used as a new natural complementary source of acetyl cholinesterase inhibitors and anti-oxidant agents, thus being a promising potential complementary source against Alzheimer's disease.

  14. Cognitive and Affective Changes in Mild to Moderate Alzheimer’s Disease Patients Undergoing Switch of Cholinesterase Inhibitors: A 6-Month Observational Study

    PubMed Central

    Spalletta, Gianfranco; Caltagirone, Carlo; Padovani, Alessandro; Sorbi, Sandro; Attar, Mahmood; Colombo, Delia; Cravello, Luca

    2014-01-01

    Patients with Alzheimer’s disease after an initial response to cholinesterase inhibitors may complain a later lack of efficacy. This, in association with incident neuropsychiatric symptoms, may worsen patient quality of life. Thus, the switch to another cholinesterase inhibitor could represent a valid therapeutic strategy. The aim of this study was to investigate the effectiveness of the switch from one to another cholinesterase inhibitor on cognitive and affective symptoms in mild to moderate Alzheimer disease patients. Four hundred twenty-three subjects were included from the EVOLUTION study, an observational, longitudinal, multicentre study conducted on Alzheimer disease patients who switched to different cholinesterase inhibitor due either to lack/loss of efficacy or response, reduced tolerability or poor compliance. All patients underwent cognitive and neuropsychiatric assessments, carried out before the switch (baseline), and at 3 and 6-month follow-up. A significant effect of the different switch types was found on Mini-Mental State Examination score during time, with best effectiveness on mild Alzheimer’s disease patients switching from oral cholinesterase inhibitors to rivastigmine patch. Depressive symptoms, when measured using continuous Neuropsychiatric Inventory values, decreased significantly, while apathy symptoms remained stable over the 6 months after the switch. However, frequency of both depression and apathy, when measured categorically using Neuropsychiatric Inventory cut-off scores, did not change significantly during time. In mild to moderate Alzheimer disease patients with loss of efficacy and tolerability during cholinesterase inhibitor treatment, the switch to another cholinesterase inhibitor may represent an important option for slowing cognitive deterioration. The evidence of apathy stabilization and the positive tendency of depressive symptom improvement should definitively be confirmed in double-blind controlled studies. PMID

  15. Discontinuation, Efficacy, and Safety of Cholinesterase Inhibitors for Alzheimer's Disease: a Meta-Analysis and Meta-Regression of 43 Randomized Clinical Trials Enrolling 16 106 Patients.

    PubMed

    Blanco-Silvente, Lídia; Castells, Xavier; Saez, Marc; Barceló, Maria Antònia; Garre-Olmo, Josep; Vilalta-Franch, Joan; Capellà, Dolors

    2017-07-01

    We investigated the effect of cholinesterase inhibitors on all-cause discontinuation, efficacy and safety, and the effects of study design-, intervention-, and patient-related covariates on the risk-benefit of cholinesterase inhibitors for Alzheimer's disease. A systematic review and meta-analysis of randomized placebo-controlled clinical trials comparing cholinesterase inhibitors and placebo was performed. The effect of covariates on study outcomes was analysed by means of meta-regression using a Bayesian framework. Forty-three randomized placebo-controlled clinical trials involving 16106 patients were included. All-cause discontinuation was higher with cholinesterase inhibitors (OR = 1.66), as was discontinuation due to adverse events (OR=1.75). Cholinesterase inhibitors improved cognitive function (standardized mean difference = 0.38), global symptomatology (standardized mean difference=0.28) and functional capacity (standardized mean difference=0.16) but not neuropsychiatric symptoms. Rivastigmine was associated with a poorer outcome on all-cause discontinuation (Diff OR = 1.66) and donepezil with a higher efficacy on global change (Diff standardized mean difference = 0.41). The proportion of patients with serious adverse events decreased with age (Diff OR = -0.09). Mortality was lower with cholinesterase inhibitors than with placebo (OR = 0.65). While cholinesterase inhibitors show a poor risk-benefit relationship as indicated by mild symptom improvement and a higher than placebo all-cause discontinuation, a reduction of mortality was suggested. Intervention- and patient-related factors modify the effect of cholinesterase inhibitors in patients with Alzheimer's disease. © The Author 2017. Published by Oxford University Press on behalf of CINP.

  16. VARIATION IN CHOLINESTERASE ACTIVITY IN TISSUES OF RATS AT DIFFERENT TIMES AFTER IRRADIATION (in Russian)

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Zubkova, S.R.; Chernavskaya, N.M.

    1959-06-11

    It was found that a single lethal dose (1000 r) changes the cholinesterase activity in the brain, liver, and blood serum. After 5 hr and 45 min the cholinesterase activity in tissues drops from the normal level (15.9% in blood serum, 20.6% in the brain, and 18.4% in the liver). After three days the activity changes in various tissues: in the liver it continues to drop, in the brain it rises but does not reach the standard level, and it increases sharply in the blood serum. (R.V.J.)

  17. Combined effect of short-term dehydration and sublethal acute oral dicrotophos exposure confounds the diagnosis of anticholinesterase exposure in common quail (Coturnix coturnix) using plasma cholinesterase activity.

    PubMed

    Heffernan, James; Mineau, Pierre; Falk, Ramona; Wickstrom, Mark

    2012-07-01

    Common Quail (Coturnix coturnix) were subjected to controlled and replicated experiments in the summer of 2008 to investigate the effects of short-term dehydration on cholinesterase activity in brain and plasma and the interaction between dehydration and exposure to the organophosphorus pesticide dicrotophos in these same tissues. Our objective was to determine if dehydration could confound the diagnosis of anticholinesterase exposure using inhibition of cholinesterase activity in quail tissues. The effect of dehydration was quantified using measures of plasma osmolality and hematocrit. Dicrotophos exposure caused significant inhibition of cholinesterase activity in brain, while the effects of dehydration and interaction were not significant. Dehydration caused significant duration-dependent increases in plasma osmolality and hematocrit. Dehydration also caused a significant increase in plasma cholinesterase activity. Variation in the change in plasma cholinesterase activity in response to dehydration was significantly and positively correlated with dehydration-induced variation in both the change in plasma osmolality and the change in hematocrit. These correlations suggest that plasma cholinesterase activity in quail is not limited to plasma but occupies some larger pool of the extracellular fluid volume, and we suggest lymph is part of that pool. The effects of dehydration on plasma cholinesterase activity masked the inhibitory effects of dicrotophos. Here, the combination of dehydration and dicrotophos exposure produced plasma cholinesterase activity that was not significantly different from reference and pre-exposure values, confounding the diagnosis of anticholinesterase exposure in dehydrated, dicrotophos-exposed quail. A method to adjust plasma cholinesterase activities for the confounding effects of dehydration and enable the diagnosis of anticholinesterase exposure in dehydrated, dicrotophos-exposed quail was developed. Clinicians and practitioners

  18. Isolation and characterization of full-length cDNA clones coding for cholinesterase from fetal human tissues

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Prody, C.A.; Zevin-Sonkin, D.; Gnatt, A.

    1987-06-01

    To study the primary structure and regulation of human cholinesterases, oligodeoxynucleotide probes were prepared according to a consensus peptide sequence present in the active site of both human serum pseudocholinesterase and Torpedo electric organ true acetylcholinesterase. Using these probes, the authors isolated several cDNA clones from lambdagt10 libraries of fetal brain and liver origins. These include 2.4-kilobase cDNA clones that code for a polypeptide containing a putative signal peptide and the N-terminal, active site, and C-terminal peptides of human BtChoEase, suggesting that they code either for BtChoEase itself or for a very similar but distinct fetal form of cholinesterase. Inmore » RNA blots of poly(A)/sup +/ RNA from the cholinesterase-producing fetal brain and liver, these cDNAs hybridized with a single 2.5-kilobase band. Blot hybridization to human genomic DNA revealed that these fetal BtChoEase cDNA clones hybridize with DNA fragments of the total length of 17.5 kilobases, and signal intensities indicated that these sequences are not present in many copies. Both the cDNA-encoded protein and its nucleotide sequence display striking homology to parallel sequences published for Torpedo AcChoEase. These finding demonstrate extensive homologies between the fetal BtChoEase encoded by these clones and other cholinesterases of various forms and species.« less

  19. Discontinuation, Efficacy, and Safety of Cholinesterase Inhibitors for Alzheimer’s Disease: a Meta-Analysis and Meta-Regression of 43 Randomized Clinical Trials Enrolling 16 106 Patients

    PubMed Central

    Blanco-Silvente, Lídia; Saez, Marc; Barceló, Maria Antònia; Garre-Olmo, Josep; Vilalta-Franch, Joan; Capellà, Dolors

    2017-01-01

    Abstract Background: We investigated the effect of cholinesterase inhibitors on all-cause discontinuation, efficacy and safety, and the effects of study design-, intervention-, and patient-related covariates on the risk-benefit of cholinesterase inhibitors for Alzheimer’s disease. Methods: A systematic review and meta-analysis of randomized placebo-controlled clinical trials comparing cholinesterase inhibitors and placebo was performed. The effect of covariates on study outcomes was analysed by means of meta-regression using a Bayesian framework. Results: Forty-three randomized placebo-controlled clinical trials involving 16106 patients were included. All-cause discontinuation was higher with cholinesterase inhibitors (OR = 1.66), as was discontinuation due to adverse events (OR=1.75). Cholinesterase inhibitors improved cognitive function (standardized mean difference = 0.38), global symptomatology (standardized mean difference=0.28) and functional capacity (standardized mean difference=0.16) but not neuropsychiatric symptoms. Rivastigmine was associated with a poorer outcome on all-cause discontinuation (Diff OR = 1.66) and donepezil with a higher efficacy on global change (Diff standardized mean difference = 0.41). The proportion of patients with serious adverse events decreased with age (Diff OR = -0.09). Mortality was lower with cholinesterase inhibitors than with placebo (OR = 0.65). Conclusion: While cholinesterase inhibitors show a poor risk-benefit relationship as indicated by mild symptom improvement and a higher than placebo all-cause discontinuation, a reduction of mortality was suggested. Intervention- and patient-related factors modify the effect of cholinesterase inhibitors in patients with Alzheimer’s disease. PMID:28201726

  20. WRAIR Protocols for Soldier Status and Readiness to Organophosphate Exposure: Unprocessed Whole Blood Cholinesterase and Pyridostigmine Bromide Quantification

    DTIC Science & Technology

    2003-07-01

    blood in the presence and absence of selective ( huperzine - a and Iso-OMPA), and non-selective (pyridostigmine bromide) cholinesterase inhibitors...cholinesterases after exposure to CWAs such as GD and pharmaceuticals such as huperzine - a and pyridostigmine have been determined in animals and man...activity. Since urban terrorism is on the rise, Federal,State, and local authorities need a reliable, fast, inexpensive method for confirming such an

  1. Efficient Synthesis and Discovery of Schiff Bases as Potent Cholinesterase Inhibitors.

    PubMed

    Razik, Basma M Abd; Osman, Hasnah; Ezzat, Mohammed O; Basiri, Alireza; Salhin, Abdussalam; Kia, Yalda; Murugaiyah, Vikneswaran

    2016-01-01

    The search for new cholinesterase inhibitors is still a promising approach for management of Alzheimer`s disease. Schiff bases are considered as important class of organic compounds, which have wide range of applications including as enzyme inhibitors. In the present study, a new green ionic liquid mediated strategy was developed for convenient synthesis of two series of Schiff bases 3(a-j) and 5(a-j) as potential cholinesterase inhibitors using aromatic aldehydes and primary amines in [bmim]Br. The synthesized compounds were evaluated for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory potential by modified Ellman's method. The molecular interactions between the most active compound and the enzyme were analyzed by molecular docking. Among them, 3j displayed higher inhibitory activities than reference drug, galanthamine, with IC50 values of 2.05 and 5.77 µM, for AChE and BChE, respectively. Interestingly, all the compounds except 3b displayed higher BChE inhibitions than galanthamine with IC50 values ranging from 5.77 to 18.52 µM. Molecular docking of compound 3j inside the TcAChE and hBChE completely coincided with the inhibitory activities observed. The compound forms strong hydrogen bonding at the peripheral anionic site of AChE whereas on BChE, it had hydrophobic and mild polar interactions. An efficient and eco-friendly synthetic methodology has been developed to synthesize Schiff bases in a very short reaction time and excellent yields in ionic solvent, whereby the compounds from series 3 showed promising cholinesterase inhibitory activity.

  2. Mechanism of inhibition of cholinesterases by Huperzine A. (Reannouncement with new availability information)

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Ashani, Y.; Peggins, J.O.; Doctor, B.P.

    1992-04-30

    Huperzine A, an alkaloid isolated from Huperzia serrata was found to reversibly inhibit acetylcholinesterases (EC 3.1.7) and (EC 3.1.1.8) with i 3.1 on- and off-rates that depend on both the type and the source of enzyme. Long incubation of high concentrations of purified (1-8 PM) with huperzine-A did not show any chemical modification of huperzine-A. A low dissociation constant K sub 1 was obtained for mammalian acetylcholinesterase-huperzine (20-40 nM) compared to mammalian butyrylcholinesterase-huperzine (20-40 microns.) This indicates that the thermodynamic stability of huperzine-cholinesterase complex may depend on the number and type of aromatic amino acid residues in the catalytic pocketmore » region of the cholinesterase molecule.« less

  3. Isolation and characterization of full-length cDNA clones coding for cholinesterase from fetal human tissues.

    PubMed Central

    Prody, C A; Zevin-Sonkin, D; Gnatt, A; Goldberg, O; Soreq, H

    1987-01-01

    To study the primary structure and regulation of human cholinesterases, oligodeoxynucleotide probes were prepared according to a consensus peptide sequence present in the active site of both human serum pseudocholinesterase (BtChoEase; EC 3.1.1.8) and Torpedo electric organ "true" acetylcholinesterase (AcChoEase; EC 3.1.1.7). Using these probes, we isolated several cDNA clones from lambda gt10 libraries of fetal brain and liver origins. These include 2.4-kilobase cDNA clones that code for a polypeptide containing a putative signal peptide and the N-terminal, active site, and C-terminal peptides of human BtChoEase, suggesting that they code either for BtChoEase itself or for a very similar but distinct fetal form of cholinesterase. In RNA blots of poly(A)+ RNA from the cholinesterase-producing fetal brain and liver, these cDNAs hybridized with a single 2.5-kilobase band. Blot hybridization to human genomic DNA revealed that these fetal BtChoEase cDNA clones hybridize with DNA fragments of the total length of 17.5 kilobases, and signal intensities indicated that these sequences are not present in many copies. Both the cDNA-encoded protein and its nucleotide sequence display striking homology to parallel sequences published for Torpedo AcChoEase. These findings demonstrate extensive homologies between the fetal BtChoEase encoded by these clones and other cholinesterases of various forms and species. Images PMID:3035536

  4. Acetamide Derivatives of Chromen-2-ones as Potent Cholinesterase Inhibitors.

    PubMed

    Prasad, Suchita; Kumar, Bipul; Kumar, Shiv; Chand, Karam; Kamble, Shashank S; Gautam, Hemant K; Sharma, Sunil K

    2017-08-01

    Alzheimer's disease (AD), a neurodegenerative disorder, is a serious medical issue worldwide with drastic social consequences. Inhibition of cholinesterase is one of the rational and effective approaches to retard the symptoms of AD and, hence, consistent efforts are being made to develop efficient anti-cholinesterase agents. In pursuit of this, a series of 19 acetamide derivatives of chromen-2-ones were synthesized and evaluated for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory potential. All the synthesized compounds exhibited significant anti-AChE and anti-BChE activity, with IC 50 values in the range of 0.24-10.19 μM and 0.64-30.08 μM, respectively, using donepezil hydrochloride as the standard. Out of 19 compounds screened, 3 compounds, viz. 22, 40, and 43, caused 50% inhibition of AChE at 0.24, 0.25, and 0.25 μM, respectively. A kinetic study revealed them to be mixed-type inhibitors, binding with both the CAS and PAS sites of AChE. The above-selected compounds were found to be effective inhibitors of AChE-induced and self-mediated Aβ 1-42 aggregation. ADMET predictions demonstrated that these compounds may possess suitable blood-brain barrier (BBB) permeability. Hemolytic assay results revealed that these compounds did not lyse human RBCs up to a thousand times of their IC 50 value. MTT assays performed for the shortlisted compounds showed them to be negligibly toxic after 24 h of treatment with the SH-SY5Y neuroblastoma cells. These results provide insights for further optimization of the scaffolds for designing the next generation of compounds as lead cholinesterase inhibitors. © 2017 Deutsche Pharmazeutische Gesellschaft.

  5. In vitro antioxidant and anti-cholinesterase activities of Rhizophora mucronata.

    PubMed

    Suganthy, N; Devi, K Pandima

    2016-01-01

    Rhizophora mucronata Lam. (Rhizophoraceae), commonly known as Asiatic mangrove, has been used traditionally among Asian countries as folk medicine. This study investigates the cholinesterase inhibitory potential and antioxidant activities of R. mucronata. Rhizophora mucronata leaves were successively extracted using solvents of varying polarity and a dosage of 100-500 µg/ml were used for each assay. Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities were assessed according to the method of Ellman. In vitro antioxidant activity was assessed using free radical scavenging, reducing power, and metal-chelating activity (duration - 3 months). Total phenolic and flavonoid content were quantified spectrophotometrically. Compound characterization was done using column chromatography, NMR, FTIR, and LC-MS analysis. Methanolic leaf extract (500 µg/ml) exhibited the highest inhibitory activity against AChE (92.73 ± 0.54%) and BuChE (98.98 ± 0.17%), with an IC50 value of 59.31 ± 0.35 and 51.72 ± 0.33 µg/ml, respectively. Among the different solvent extracts, methanolic extract exhibited the highest antioxidant activity with an IC50 value of 47.39 ± 0.43, 401.45 ± 18.52, 80.23 ± 0.70, and 316.47 ± 3.56 µg/ml for DPPH, hydroxyl, nitric oxide radical, and hydrogen peroxide, respectively. Total polyphenolic and flavonoid contents in methanolic extract were observed to be 598.13 ± 1.85 µg of gallic acid equivalent and 48.85 ± 0.70 μg of rutin equivalent/mg of extract. Compound characterization illustrated (+)-catechin as the bioactive compound responsible for cholinesterase inhibitory and antioxidant activities. The presence of rich source of flavonoids, in particular catechin, might be responsible for its cholinesterase inhibitory and antioxidant activities.

  6. Influence of cholinesterase inhibitors, donepezil and rivastigmine on the acquisition, expression, and reinstatement of morphine-induced conditioned place preference in rats.

    PubMed

    Gawel, Kinga; Labuz, Krzysztof; Jenda, Malgorzata; Silberring, Jerzy; Kotlinska, Jolanta H

    2014-07-15

    The influence of systemic administration of cholinesterase inhibitors, donepezil and rivastigmine on the acquisition, expression, and reinstatement of morphine-induced conditioned place preference (CPP) was examined in rats. Additionally, this study aimed to compare the effects of donepezil, which selectively inhibits acetylcholinesterase, and rivastigmine, which inhibits both acetylcholinesterase and butyrylcholinesterase on morphine reward. Morphine-induced CPP (unbiased method) was induced by four injections of morphine (5 mg/kg, i.p.). Donepezil (0.5, 1, and 3 mg/kg, i.p.) or rivastigmine (0.03, 0.5, and 1 mg/kg, i.p.) were given 20 min before morphine during conditioning phase and 20 min before the expression or reinstatement of morphine-induced CPP. Our results indicated that both inhibitors of cholinesterase attenuated the acquisition and expression of morphine CPP. The results were more significant after rivastigmine due to a broader inhibitory spectrum of this drug. Moreover, donepezil (1 mg/kg) and rivastigmine (0.5 mg/kg) attenuated the morphine CPP reinstated by priming injection of 5mg/kg morphine. These properties of both cholinesterase inhibitors were reversed by mecamylamine (3 mg/kg, i.p.), a nicotinic acetylcholine receptor antagonist but not scopolamine (0.5 mg/kg, i.p.), a muscarinic acetylcholine receptor antagonist. All effects of cholinesterase inhibitors were observed at the doses that had no effects on locomotor activity of animals. Our results suggest beneficial role of cholinesterase inhibitors in reduction of morphine reward and morphine-induced seeking behavior. Finally, we found that the efficacy of cholinesterase inhibitors in attenuating reinstatement of morphine CPP provoked by priming injection may be due to stimulation of nicotinic acetylcholine receptors. Copyright © 2014 Elsevier B.V. All rights reserved.

  7. Suitability of cholinesterase of polychaete Diopatra neapolitana as biomarker of exposure to pesticides: In vitro characterization.

    PubMed

    Mennillo, Elvira; Casu, Valentina; Tardelli, Federica; De Marchi, Lucia; Freitas, Rosa; Pretti, Carlo

    2017-01-01

    Cholinesterases of Diopatra neapolitana were characterized for their activity in whole body and different body segments (apical, intermediate, posterior), substrate affinity (acetyl-, butyryl-, propionylthiocholine), kinetic parameters (K m and V max ) and in vitro response to model inhibitors (eserine hemisulfate, isoOMPA, BW284C51) and carbamates (carbofuran, methomyl, aldicarb and carbaryl). Results showed that the rate of hydrolysis for acetyl- and propionylthiocholine was higher in the posterior segment than the apical/intermediate segments and whole body. Cholinesterases of D. neapolitana showed a substrate preference for acetylthiocholine followed by propionylthiocholine; butyrylthioline was poorly hydrolyzed indicating, together with the absence of inhibition by the specific inhibitor and the absence of reactive bands in native electrophoresis, a lack of an active butyrylcholinesterase, differently than that observed in other Annelida species. The degree of inhibition by selected carbamates of cholinesterase activity with propionylthiocholine as substrate was higher than that observed with ATChI-ChE activity; aldicarb showed the highest inhibitory effect. Copyright © 2016 Elsevier Inc. All rights reserved.

  8. Cholinesterase inhibition and acetylcholine accumulation following intracerebral administration of paraoxon in rats

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Ray, A.; Liu, J.; Karanth, S.

    2009-05-01

    We evaluated the inhibition of striatal cholinesterase activity following intracerebral administration of paraoxon assaying activity either in tissue homogenates ex vivo or by substrate hydrolysis in situ. Artificial cerebrospinal fluid (aCSF) or paraoxon in aCSF was infused unilaterally (0.5 {mu}l/min for 2 h) and ipsilateral and contralateral striata were harvested for ChE assay ex vivo. High paraoxon concentrations were needed to inhibit ipsilateral striatal cholinesterase activity (no inhibition at < 0.1 mM; 27% at 0.1 mM; 79% at 1 mM paraoxon). With 3 mM paraoxon infusion, substantial ChE inhibition was also noted in contralateral striatum. ChE histochemistry generally confirmed thesemore » concentration- and side-dependent effects. Microdialysates collected for up to 4 h after paraoxon infusion inhibited ChE activity when added to striatal homogenate, suggesting prolonged efflux of paraoxon. Since paraoxon efflux could complicate acetylcholine analysis, we evaluated the effects of paraoxon (0, 0.03, 0.1, 1, 10 or 100 {mu}M, 1.5 {mu}l/min for 45 min) administered by reverse dialysis through a microdialysis probe. ChE activity was then monitored in situ by perfusing the colorimetric substrate acetylthiocholine through the same probe and measuring product (thiocholine) in dialysates. Concentration-dependent inhibition was noted but reached a plateau of about 70% at 1 {mu}M and higher concentrations. Striatal acetylcholine was below the detection limit at all times with 0.1 {mu}M paraoxon but was transiently elevated (0.5-1.5 h) with 10 {mu}M paraoxon. In vivo paraoxon (0.4 mg/kg, sc) in adult rats elicited about 90% striatal ChE inhibition measured ex vivo, but only about 10% inhibition measured in situ. Histochemical analyses revealed intense AChE and glial fibrillary acidic protein staining near the cannula track, suggesting proliferation of inflammatory cells/glia. The findings suggest that ex vivo and in situ cholinesterase assays can provide very

  9. Prognostic Factors in Cholinesterase Inhibitor Poisoning.

    PubMed

    Sun, In O; Yoon, Hyun Ju; Lee, Kwang Young

    2015-09-28

    Organophosphates and carbamates are insecticides that are associated with high human mortality. The purpose of this study is to investigate the prognostic factors affecting survival in patients with cholinesterase inhibitor (CI) poisoning. This study included 92 patients with CI poisoning in the period from January 2005 to August 2013. We divided these patients into 2 groups (survivors vs. non-survivors), compared their clinical characteristics, and analyzed the predictors of survival. The mean age of the included patients was 56 years (range, 16-88). The patients included 57 (62%) men and 35 (38%) women. When we compared clinical characteristics between the survivor group (n=81, 88%) and non-survivor group (n=11, 12%), there were no differences in renal function, pancreatic enzymes, or serum cholinesterase level, except for serum bicarbonate level and APACHE II score. The serum bicarbonate level was lower in non-survivors than in survivors (12.45±2.84 vs. 18.36±4.73, P<0.01). The serum APACHE II score was higher in non-survivors than in survivors (24.36±5.22 vs. 12.07±6.67, P<0.01). The development of pneumonia during hospitalization was higher in non-survivors than in survivors (n=9, 82% vs. n=31, 38%, P<0.01). In multiple logistic regression analysis, serum bicarbonate concentration, APACHE II score, and pneumonia during hospitalization were the important prognostic factors in patients with CI poisoning. Serum bicarbonate and APACHE II score are useful prognostic factors in patients with CI poisoning. Furthermore, pneumonia during hospitalization was also important in predicting prognosis in patients with CI poisoning. Therefore, prevention and active treatment of pneumonia is important in the management of patients with CI poisoning.

  10. Zectran fed orally to mice...cholinesterase levels in blood determined

    Treesearch

    Jean Marie Lang; Raymond R. Miskus

    1967-01-01

    Zectran, a carbamate insecticide, is being field-tested against the spruce budworm. Taken in sufficient quantity, it can induce cholinesterase (ChE) inhibition in mammals. In laboratory experiments, Zectran was fed orally to mice. Results indicated that maximum ChE inhibition occurred 15 to 30 minutes after ingestion of Zectran, and that a ChE test is unreliable in the...

  11. The distribution of cholinesterases in the cat carotid body

    PubMed Central

    Biscoe, T. J.; Silver, Ann

    1966-01-01

    1. The distribution of acetyl- and butyrylcholinesterase in the carotid body of the cat has been examined histochemically. Studies were made on normal carotid bodies and on carotid bodies from cats in which certain nerves had been cut some time previously. The nerves sectioned were the sinus nerve, the post-ganglionic sympathetic branch of the superior cervical ganglion or the preganglionic cervical sympathetic trunk. 2. It was confirmed that more butyrylcholinesterase than acetylcholinesterase is present. Both enzymes are found in three sites: (i) as strands, (ii) as plexuses, (iii) inside a few cells. 3. The distribution is unaffected by cutting the sinus nerve or preganglionic cervical sympathetic nerves. Disorganization and depletion of the cholinesterases in the strands and plexuses occurs when the post-ganglionic branch of the superior cervical ganglion is cut. The cholinesterase in cells is unaffected. 4. In carotid bodies in which vessels were filled with red blood cells or in which the vascular bed was injected with carmine-gelatine, it was seen that strands and plexuses are associated with blood vessels, and with blood vessels and cells respectively. 5. It is suggested that a cholinergic pathway controlling carotid body blood vessels runs in the post-ganglionic cervical sympathetic. ImagesabcdefPlate 2abcdef PMID:5942823

  12. The distribution of cholinesterases in the cat carotid body.

    PubMed

    Biscoe, T J; Silver, A

    1966-03-01

    1. The distribution of acetyl- and butyrylcholinesterase in the carotid body of the cat has been examined histochemically. Studies were made on normal carotid bodies and on carotid bodies from cats in which certain nerves had been cut some time previously. The nerves sectioned were the sinus nerve, the post-ganglionic sympathetic branch of the superior cervical ganglion or the preganglionic cervical sympathetic trunk.2. It was confirmed that more butyrylcholinesterase than acetylcholinesterase is present. Both enzymes are found in three sites: (i) as strands, (ii) as plexuses, (iii) inside a few cells.3. The distribution is unaffected by cutting the sinus nerve or preganglionic cervical sympathetic nerves. Disorganization and depletion of the cholinesterases in the strands and plexuses occurs when the post-ganglionic branch of the superior cervical ganglion is cut. The cholinesterase in cells is unaffected.4. In carotid bodies in which vessels were filled with red blood cells or in which the vascular bed was injected with carmine-gelatine, it was seen that strands and plexuses are associated with blood vessels, and with blood vessels and cells respectively.5. It is suggested that a cholinergic pathway controlling carotid body blood vessels runs in the post-ganglionic cervical sympathetic.

  13. Effect of pomegranate extracts on brain antioxidant markers and cholinesterase activity in high fat-high fructose diet induced obesity in rat model.

    PubMed

    Amri, Zahra; Ghorbel, Asma; Turki, Mouna; Akrout, Férièle Messadi; Ayadi, Fatma; Elfeki, Abdelfateh; Hammami, Mohamed

    2017-06-27

    To investigate beneficial effects of Pomegranate seeds oil (PSO), leaves (PL), juice (PJ) and (PP) on brain cholinesterase activity, brain oxidative stress and lipid profile in high-fat-high fructose diet (HFD) induced-obese rat. In vitro and in vivo cholinesterase activity, brain oxidative status, body and brain weight and plasma lipid profile were measured in control rats, HFD-fed rats and HFD-fed rats treated by PSO, PL, PJ and PP. In vitro study showed that PSO, PL, PP, PJ inhibited cholinesterase activity in dose dependant manner. PL extract displayed the highest inhibitory activity by IC50 of 151.85 mg/ml. For in vivo study, HFD regime induced a significant increase of cholinesterase activity in brain by 17.4% as compared to normal rats. However, the administration of PSO, PL, PJ and PP to HDF-rats decreased cholinesterase activity in brain respectively by 15.48%, 6.4%, 20% and 18.7% as compared to untreated HFD-rats. Moreover, HFD regime caused significant increase in brain stress, brain and body weight, and lipid profile disorders in blood. Furthermore, PSO, PL, PJ and PP modulated lipid profile in blood and prevented accumulation of lipid in brain and body evidenced by the decrease of their weights as compared to untreated HFD-rats. In addition administration of these extract protected brain from stress oxidant, evidenced by the decrease of malondialdehyde (MDA) and Protein carbonylation (PC) levels and the increase in superoxide dismutase (SOD) and glutathione peroxidase (GPx) levels. These findings highlight the neuroprotective effects of pomegranate extracts and one of mechanisms is the inhibition of cholinesterase and the stimulation of antioxidant capacity.

  14. Antibacterial, antioxidant, anti-cholinesterase potential and flavonol glycosides of Biscutella raphanifolia (Brassicaceae).

    PubMed

    Boudouda, Houria Berhail; Zeghib, Assia; Karioti, Anastazia; Bilia, Anna Rita; Öztürk, Mehmet; Aouni, Mahjoub; Kabouche, Ahmed; Kabouche, Zahia

    2015-01-01

    Different extracts of the aerial parts of Biscutella raphanifolia (Brassicaceae), which has not been the subject of any study, were screened for the phytochemical content, anti-microbial, antioxidant and anti-cholinesterase activities. We used four methods to identify the antioxidant activity namely, ABTS(•+), DPPH• scavenging, CUPRAC and ferrous-ions chelating methods. Since there is a relationship between antioxidants and cholinesterase enzyme inhibitors, we used two methods to determine the in vitro anti-cholinesterase activity by the use of the basic enzymes that occur in causing Alzheimer's disease: acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The extracts were also tested in vitro antimicrobial activity against various bacteria. The phytochemical study of B. raphanifolia afforded four flavonol glycosides; namely, quercetin-3-O-β-D-g1ucoside, quercetin-3-O-[β-D-glucosyl(1→2)-O-β-D-glucoside], quercetin-3-O-[β-D-glucosyl(1→3)-O-β-D-glucoside] and kaempferol-3-O-[β-D-glucosyl(1→2)-[(6'''p-coumaroyl)- β-D-glucoside], being isolated here for the first time from Biscutella raphanifolia and the genus. The ethyl acetate extract showed the highest activity in ABTS(•+), DPPH• and CUPRAC assays, while the petroleum ether extract demonstrated optimum efficiency metal chelating activity. The dicloromethane and petroleum ether extracts showed a mild inhibition against AChE and BChE. However, the petroleum ether extract showed a good antibacterial activity against the pathovars Enteropathogenic E. coli (EPEC), Enterotoxigenic E. coli (ETEC) and Enterococcus feacalis, whereas the Enterohemorrhagic E. coli (EHEC) strain was more sensitive to dichloromethane and n-butanol extracts.

  15. Cholinesterases inhibition and molecular modeling studies of piperidyl-thienyl and 2-pyrazoline derivatives of chalcones.

    PubMed

    Shah, Muhammad Shakil; Khan, Shafi Ullah; Ejaz, Syeda Abida; Afridi, Saifullah; Rizvi, Syed Umar Farooq; Najam-Ul-Haq, Muhammad; Iqbal, Jamshed

    2017-01-22

    Super-activation of cholinesterases (acetylcholinesterase and butyrylcholinesterase) are linked to various neurological problems most precisely Alzheimer's disease (AD), which leads to senile dementia. Therefore, cholinesterases (AChE & BChE) inhibition are considered as a promising strategy for the treatment of Alzheimer's disease. FDA approved drugs for the treatment of AD, belong to a group of cholinesterase inhibitors. However, none of them is able to combat or completely abrogate the disease progression. Herein, we report a series of newly synthesized chalcone derivatives with anti-AD potential. For this purpose, a series of piperidyl-thienyl and 2-pyrazoline derivatives of chalcones were tested for their cholinesterases (AChE & BChE) inhibitory activity. All compounds were found as selective inhibitor of AChE. In piperidyl chalcones derivatives compound 1e having IC 50 of 0.16 ± 0.008 μM and 2m in 2-pyrazoline chalcones with IC 50 of 0.13 ± 0.006 μM, were found to be the most potent inhibitors of AChE, exhibiting ≈142 and ≈ 173-fold greater inhibitory potential compared to the reference inhibitor i.e., Neostigmine (IC 50  ± SEM = 22.2 ± 3.2 μM). Molecular docking studies of most potent inhibitors were carried out to investigate the binding interactions inside the active site. Molecular docking study revealed that potent compounds and co-crystalized ligand had same binding orientation within the active site of target enzyme. Most of these compounds are selective inhibitors of AChE with a potential use against progressive neurodegenerative disorder and age related problems. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. Effect of methylmercury on acetylcholinestrase and serum cholinesterase activity in monkeys, Macaca fascicularis

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Petruccioli, L.; Turillazzi, P.G.

    1991-05-01

    The consumption of fish and fish-derived products is the main pathway of human exposure to methylmercury (MeHg). Methylmercury levels vary widely in fish, depending on age, size, the position of the species in the food chain, and most of all, on pollution levels. MeHg affects the Acetylcholinesterase activity (AChE) and the serum Cholinesterase activity (BChE). Histoenzymatic studies showed that 100mg Methyoxyethylmercury chloride administered for 6 days to rats caused a reduction of AChE activity in the thalamus and an increase in different parts of the nervous central system. The present study aims at verifying whether the dose permitted by F.A.O.more » and doses 10 and 100 fold higher affect the Cholinesterase activity in primates, and whether there is a correlation between AChE and BChE.« less

  17. The Activity of Cholinesterases in Diapausing and Flying Red Mason Bees Osmia bicornis (Megachilidae).

    PubMed

    Dmochowska-Slezak, Kamila; Zaobidna, Ewa; Domeracka, Joanna; Swiatkowska, Marta; Rusznica, Małgorzata; Zółtowska, Krystyna

    2015-01-01

    The red mason bee (Osmia bicornis) is a highly effective pollinator that is exposed to various xenobiotics. The organism's potential resistance to the toxic effects of xenobiotics can be determined based on cholinesterase activity. The activity of cholinesterases (ChEs) towards acetylcholine (ACh) and butyrylcholine (BCh) was determined in extracts of diapausing (between October and late March) and flying bees (May). In both males and females, enzyme activity was higher towards ACh than towards BCh. The ratio of ACh/BCh activity was determined in the range of 1.43 to 4.15 in diapausing females and 3.00 to 7.18 in diapausing males. No significant changes in ChE activity towards ACh were observed in females before December and in males before February. Enzyme activity towards ACh increased dynamically in the second half of March. Enzyme activity towards BCh remained stable in both sexes until mid-March, after which it increased significantly. Excluding mid-March, enzyme BCh activity was significantly higher in females than in males. The activity of carboxylesterase towards 4-p-nitrophenyl butyrate was determined in females to assess the involvement of non-specific esterases in the hydrolysis of choline esters. Carboxylesterase activity was low in comparison with cholinesterase activity, and it remained practically unchanged throughout diapause, suggesting that choline esters in female O. bicornis extracts were hydrolyzed mainly by acetylcholinesterases.

  18. Discorhabdin alkaloids from Antarctic Latrunculia spp. sponges as a new class of cholinesterase inhibitors.

    PubMed

    Botić, Tanja; Defant, Andrea; Zanini, Pietro; Žužek, Monika Cecilija; Frangež, Robert; Janussen, Dorte; Kersken, Daniel; Knez, Željko; Mancini, Ines; Sepčić, Kristina

    2017-08-18

    The brominated pyrroloiminoquinone alkaloids discorhabdins B, L and G and 3-dihydro-7,8- dehydrodiscorhabdin C, isolated from methanol extracts of two specimens of Latrunculia sp. sponges collected near the Antarctic Peninsula, are here demonstrated for the first time to be reversible competitive inhibitors of cholinesterases. They showed K i for electric eel acetylcholinesterase of 1.6-15.0 μM, for recombinant human acetylcholinesterase of 22.8-98.0 μM, and for horse serum butyrylcholinesterase of 5.0-76.0 μM. These values are promising when compared to the current cholinesterase inhibitors used for treatment of patients with Alzheimer's disease, to counteract the acetylcholine deficiency in the brain. Good correlation was obtained between IC 50 data and results by molecular docking calculation on the binding interactions within the acetylcholinesterase active site, which also indicated the moieties in discorhabdin structures involved. To avoid unwanted peripheral side effects that can appear in patients using some acetylcholinesterase inhibitors, electrophysiological experiments were carried out on one of the most active of these compounds, discorhabdin G, which confirmed that it had no detectable undesirable effects on neuromuscular transmission and skeletal muscle function. These findings are promising for development of cholinesterase inhibitors based on the scaffold of discorhabdins, as potential new agents for treatment of patients with Alzheimer's disease. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  19. Quantitative estimation of cholinesterase-specific drug metabolism of carbamate inhibitors provided by the analysis of the area under the inhibition-time curve.

    PubMed

    Zhou, Huimin; Xiao, Qiaoling; Tan, Wen; Zhan, Yiyi; Pistolozzi, Marco

    2017-09-10

    Several molecules containing carbamate groups are metabolized by cholinesterases. This metabolism includes a time-dependent catalytic step which temporary inhibits the enzymes. In this paper we demonstrate that the analysis of the area under the inhibition versus time curve (AUIC) can be used to obtain a quantitative estimation of the amount of carbamate metabolized by the enzyme. (R)-bambuterol monocarbamate and plasma butyrylcholinesterase were used as model carbamate-cholinesterase system. The inhibition of different concentrations of the enzyme was monitored for 5h upon incubation with different concentrations of carbamate and the resulting AUICs were analyzed. The amount of carbamate metabolized could be estimated with <15% accuracy (RE%) and ≤23% precision (RSD%). Since the knowledge of the inhibition kinetics is not required for the analysis, this approach could be used to determine the amount of drug metabolized by cholinesterases in a selected compartment in which the cholinesterase is confined (e.g. in vitro solutions, tissues or body fluids), either in vitro or in vivo. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Early effects of whole body irradiation on cholinesterase activity in guinea-pigs' blood, with special regard to radiation sickness

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Lundin, J; Clemedson, C -J; Nelson, A

    1957-07-01

    Male guinea-pigs suffered a loss of cholinesterase activity in plasma amounting to about 30% during the first two days after whole-body roentgen irradiation with 400 r. No changes in the activity of acetylcholinesterase in erythrocytes to be ascribed to the irradiation could be demonstrated during the first two days. A routine method for determination of the cholinesterase activities has been tested but is found less suitable as a diagnostic tool for the early recognition of the effects of irradiation.

  1. In vitro kinetic interactions of DEET, pyridostigmine and organophosphorus pesticides with human cholinesterases.

    PubMed

    Wille, Timo; Thiermann, Horst; Worek, Franz

    2011-04-25

    The simultaneous use of the repellent DEET, pyridostigmine, and organophosphorus pesticides has been assumed as a potential cause for the Gulf War Illness and combinations have been tested in different animal models. However, human in vitro data on interactions of DEET with other compounds are scarce and provoked the present in vitro study scrutinizing the interactions of DEET, pyridostigmine and pesticides with human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBChE). DEET showed to be a weak and reversible inhibitor of hAChE and hBChE. The IC(50) of DEET was calculated to be 21.7mM DEET for hAChE and 3.2mM DEET for hBChE. The determination of the inhibition kinetics of pyridostigmine, malaoxon and chlorpyrifos oxon with hAChE in the presence of 5mM DEET resulted in a moderate reduction of the inhibition rate constant k(i). The decarbamoylation velocity of pyridostigmine-inhibited hAChE was not affected by DEET. In conclusion, the in vitro investigation of interactions between human cholinesterases, DEET, pyridostigmine, malaoxon and chlorpyrifos oxon showed a weak inhibition of hAChE and hBChE by DEET. The inhibitory potency of the tested cholinesterase inhibitors was not enhanced by DEET and it did not affect the regeneration velocity of pyridostigmine-inhibited AChE. Hence, this in vitro study does not give any evidence of a synergistic effect of the tested compounds on human cholinesterases. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  2. [Inhibitory effect of benzimidazole derivatives on cholinesterases of animals in the presence of different substrates].

    PubMed

    Basova, N E; Kormilitsyn, B N; Perchenok, A Iu; Rosengart, E V; Saakov, V S; Suvorov, A A

    2014-01-01

    Specifically synthesized group of benzimidazole derivatives possessing varying degrees of delocalization of the positive charge in the cation group of the molecule has been studied in order to search for potential cholinergically active compounds and to study the role of the Coulomb interaction in cholinesterase catalysis. These compounds were reversible inhibitors of cholinesterase (ChE) of human erythrocytes, horse serum, brain of the frog Rana temporaria and visual ganglia of the Pacific squid Todarodes pacificus in the presence of acetylthiocholine iodide and propionylthiocholine iodide as substrates. The differences in the nature of reversible inhibitory effect were observed. The effect of the inhibitor structure and substrate nature, specific for each of the studied inhibitors, on the character of the process of reversible inhibition was found.

  3. Structural analysis of the asparagine-linked oligosaccharides of cholinesterases. N-linked carbohydrates of cholinesterases

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Saxena, A.; Doctor, B.P.

    1995-12-31

    Cholinesterases are serine esterases that hydrolyse choline esters faster than other substrates. They are highly glycosylated proteins with up to 24% of their molecular weight constituted of carbohydrates. Here we report the results of our studies on the glycosylation of fetal bovine serum acetylcholinesterase (FBS AChE) and horse serum butyrylcholinesterase (Eq BChE). Analysis of the monosaccharide content of the two enzymes indicated that Eq BChE contained 520 nmoles of monosaccharide/mg protein, as compared to 1290 nmoles/mg protein for Eq BChE. Both enzymes contained mannose, galactose, N-acetylglucosamine and sialic acid. Fucose was present in Eq BChE only. The structures of themore » two major oligosaccharides from FBS AChE and one major oligosaccharide from Eq BChE were determined and found to be very similar except that one of the oligosaccharides from FBS AChE contained a galactose alphal-3 galactose betal-4-determinant which has been identified as a potentially immunogenic determinant.« less

  4. Actions of the selective inhibitor of cholinesterase tetramonoisopropyl pyrophosphortetramide on the rat phrenic nerve-diaphragm preparation

    PubMed Central

    Heffron, P. F.

    1972-01-01

    1. Tetramonoisopropyl pyrophosphortetramide (iso-OMPA) added for 15 min to the rat isolated phrenic nerve-diaphragm in a concentration of 30 μM, produced a complete selective and stable inhibition of cholinesterase. A concentration of 3 μM produced near complete inhibition of cholinesterase, and a concentration of 300 μM also inhibited acetylcholinesterase marginally. 2. Inhibition of cholinesterase was associated with a sustained increase in the neuromuscular blocking action of exogenous butyrylcholine but not of exogenous acetylcholine. Iso-OMPA, 300 μM, in addition caused transient increases in the sensitivity of the rat diaphragm to exogenous acetylcholine and butyrylcholine. In the same concentration, it had a curare-like action on the frog rectus abdominis muscle preparation. 3. Iso-OMPA, 30 μM, caused reversible increases in the amplitude of the twitch response and tetanic responses, which were of a similar magnitude in the indirectly stimulated preparation and the directly stimulated curarized preparation. Caffeine had a similar effect on the twitch response and its effectiveness was increased by iso-OMPA, and vice-versa. Amongst anticholinesterases, octamethyl pyrophosphortetramide and tetraethylpyrophosphate also enhanced the amplitude of the tetanic response, but paraoxon, dyflos, and mipafox did not. 4. It is concluded that iso-OMPA, in concentrations (3 and 30 μM) which in 15 min give near maximal or maximal selective inhibition of cholinesterase, has no effect on the transmission of nerve impulses at the neuromuscular junction, but enhances reversibly the amplitude of the contractile response to stimulation by a direct action upon the muscle fibre, which involves a mechanism related to but not identical with that by which caffeine potentiates twitch tension. In higher concentrations, iso-OMPA has a curare-like action at the neuromuscular junction. PMID:4347708

  5. Cholinesterase enzymes inhibitors from the leaves of Rauvolfia reflexa and their molecular docking study.

    PubMed

    Fadaeinasab, Mehran; Hadi, A Hamid A; Kia, Yalda; Basiri, Alireza; Murugaiyah, Vikneswaran

    2013-03-25

    Plants of the Apocynaceae family have been traditionally used in the treatment of age-related brain disorders. Rauvolfia reflexa, a member of the family, has been used as an antidote for poisons and to treat malaria. The dichloromethane, ethanol and methanol extracts from the leaves of Rauvolfia reflexa showed potential acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities, with IC50 values in the 8.49 to 52.23 g/mL range. Further cholinesterase inhibitory-guided isolation of these extracts afforded four bioactive compounds, namely: (E)-3-(3,4,5-trimethoxyphenyl)acrylic acid (1), (E)-methyl 3-(4-hydroxy-3,5-dimethoxyphenyl) acrylate (2), 17-methoxycarbonyl-14-heptadecaenyl-4-hydroxy-3-methoxycinnamate (3) and 1,2,3,4-tetrahydro-1-oxo-β-carboline (4). The isolated compounds showed moderate cholinesterase inhibitory activity compared to the reference standard, physostigmine. Compounds 1 and 2 showed the highest inhibitory activity against AChE (IC50 = 60.17 µM) and BChE (IC50 = 61.72 µM), respectively. Despite having similar molecular weight, compounds 1 and 2 were structurally different according to their chemical substitution patterns, leading to their different enzyme inhibition selectivity. Compound 2 was more selective against BChE, whereas compound 1 was a selective inhibitor of AChE. Molecular docking revealed that both compounds 1 and 2 were inserted, but not deeply into the active site of the cholinesterase enzymes.

  6. Synthesis, cytotoxicity and molecular modelling studies of new phenylcinnamide derivatives as potent inhibitors of cholinesterases.

    PubMed

    Saeed, Aamer; Mahesar, Parvez Ali; Zaib, Sumera; Khan, Muhammad Siraj; Matin, Abdul; Shahid, Mohammad; Iqbal, Jamshed

    2014-05-06

    The present study reports the synthesis of cinnamide derivatives and their biological activity as inhibitors of both cholinesterases and anticancer agents. Controlled inhibition of brain acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) may slow neurodegeneration in Alzheimer's diseases (AD). The anticholinesterase activity of phenylcinnamide derivatives was determined against Electric Eel acetylcholinesterase (EeAChE) and horse serum butyrylcholinesterase (hBChE) and some of the compounds appeared as moderately potent inhibitors of EeAChE and hBChE. The compound 3-(2-(Benzyloxy)phenyl)-N-(3,4,5-trimethoxyphenyl)acrylamide (3i) showed maximum activity against EeAChE with an IC50 0.29 ± 0.21 μM whereas 3-(2-chloro-6-nitrophenyl)-N-(3,4,5-trimethoxyphenyl)acrylamide (3k) was proved to be the most potent inhibitor of hBChE having IC50 1.18 ± 1.31 μM. To better understand the enzyme-inhibitor interaction of the most active compounds toward cholinesterases, molecular modelling studies were carried out on high-resolution crystallographic structures. The anticancer effects of synthesized compounds were also evaluated against cancer cell line (lung carcinoma). The compounds may be useful leads for the design of a new class of anticancer drugs for the treatment of cancer and cholinesterase inhibitors for Alzheimer's disease (AD). Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  7. The kinetic study of the inhibition of human cholinesterases by demeton-S-methyl shows that cholinesterase-based titration methods are not suitable for this organophosphate.

    PubMed

    Bazire, Alexandre; Gillon, Emilie; Lockridge, Oksana; Vallet, Virginie; Nachon, Florian

    2011-04-01

    The organophosphorus insecticide, demeton-S-methyl (DSM), is considered as a good surrogate of the highly toxic nerve agent VX for skin absorption studies due to similar physico-chemical properties and in vitro percutaneous penetration profile. But, when skin distribution was estimated by measuring inhibition of cholinesterase activity, the results were poorly reproducible. The various grades of commercial DSM solutions were suspected to be the origin of the discrepancies. This hypothesis was tested by measuring inhibition of human acetyl- and butyrylcholinesterase by two commercial DSM solutions. The inhibition rate was independent on the enzyme concentration confirming pseudo-first order conditions. But complete inhibition of butyrylcholinesterase activity was achieved only when the DSM concentration was at least 1500-fold higher than the enzyme concentration. Besides, complete inhibition of acetylcholinesterase was never achieved. Mass spectrometry analysis of the inhibited butyrylcholinesterase adducts identified monomethoxyphosphorylated-serine, the aged product of inhibition by DSM or a derivative with a modified leaving group. Neither spontaneous reactivation nor aging of the dimethoxyphosphorylated-serine could account for the inhibition kinetics observed, suggesting an overly complicated kinetic scheme not compatible with the requirement of a titration experiment. In conclusion, cholinesterase-based analytical methods should be avoided for DSM titration in skin penetration studies. Copyright © 2011 Elsevier Ltd. All rights reserved.

  8. [Insect cholinesterases and irreversible inhibitors. Statistical treatment of the data].

    PubMed

    Moralev, S N

    2010-01-01

    The data on sensitivity of cholinesterases (ChE) of different insects to reversible inhibitors, as well as the data on physico-chemical parameters of amino acids constituting their active centers, were treated by factor analysis and juxtaposed. It is shown that both these characteristics are related to taxonomical belonging of insects. It is revealed the "material substrate" of the factors determining inhibitor action specificity, which are specific sites in ChE active center.

  9. Synthesis, kinetic studies and molecular modeling of novel tacrine dimers as cholinesterase inhibitors.

    PubMed

    de Aquino, Roney Anderson Nascimento; Modolo, Luzia Valentina; Alves, Rosemeire Brondi; de Fátima, Ângelo

    2013-12-28

    This study presents the synthesis of 15 new tacrine dimers as well as the Ki and IC50 results, studies of the kinetic mechanism, and molecular docking analysis of the dimers in relation to the cholinesterases hAChE, hBChE, EeAChE and eqBChE. In addition to spectroscopic characterization, X-ray structure determination was performed for two of the new compounds. These new dimers were found to be mixed nanomolar inhibitors of the evaluated targets with a broad and significant selectivity profile, and these properties are dependent on both the type of the linker and the volume of the hydroacridine alicyclic ring. The results indicate that the aromatic linkers play a significant role in generating specific interactions with the half-gorge region of the catalytic center. Thus, these types of linkers can positively modulate the electronic properties of the tacrine dimers studied with an improvement of their cholinesterase inhibition activity.

  10. Association between blood cholinesterase activity, organophosphate pesticide residues on hands, and health effects among chili farmers in Ubon Ratchathani Province, northeastern Thailand

    PubMed

    Nganchamung, Thitirat; Robson, Mark G; Siriwong, Wattasit

    Use of pesticides has been documented to lead to several adverse health effects. Farmers are likely to be exposed to pesticides through dermal exposure as a result of mixing, loading, and spraying. Organophosphate pesticides (OPs) are widely used in most of the agricultural areas throughout Thailand. OPs are cholinesterase inhibitors and blood cholinesterase activity is used as a biomarker of OP effects. This study aims to determine the association between blood cholinesterase activity and organophosphate pesticide residues on chili farmer’s hands and their adverse health effects. Ninety chili farmers directly involved with pesticide applications (e.g. mixing, loading, spraying) were recruited and were interviewed face to face. Both enzymes, erythrocyte acetylcholinesterase (AChE) and plasma cholinesterase (PChE), were tested with the EQM Test-mate Cholinesterase Test System (Model 400). Hand wipe samples were used for collecting residues on both hands and OP residues for chlorpyrifos and profenofos were quantified using gas chromatography equipped with a flame photometric detector (GC-FPD). The average activity (±SD) of AChE and PChE was 2.73 (±0.88) and 1.58 (±0.56) U/mL, respectively. About 80.0% of the participants had detectable OP residues on hands. The median residues of chlorpyrifos and profenofos were found to be 0.02 and 0.03 mg/kg/two hands, respectively. Half of participants reported having some acute health symptoms within 48 hours after applying pesticides. When adjusted for gender, number of years working in chili farming, and frequency of pesticide use, AChE activity (Adjusted OR = 0.03, 95%CI: 0.01-0.13) and detected OP residues on hands (Adjusted OR = 0.15, 95%CI: 0.02-0.95) were significantly associated with having health effects, but no significant association was found in PChE activity (Adjusted OR = 2.09, 95%CI: 0.63-6.99). This study suggests that regular monitoring for blood cholinesterase and effective interventions to reduce pesticide

  11. Pesticide Exposure and Cholinesterase Levels in Migrant Farm Workers in Thailand.

    PubMed

    Thetkathuek, Anamai; Yenjai, Pornthip; Jaidee, Wanlop; Jaidee, Patchana; Sriprapat, Poonsak

    2017-01-01

    In this study, we examined the effects of pesticides in migrant farm workers from Cambodia after workplace exposure on fruit plantations in eastern Thailand. We studied 891 migrant farm workers employed on pineapple, durian, and rambutan plantations in Thailand. Data were collected via a detailed questionnaire survey and measurements of serum cholinesterase level (SChE). The majority of subjects was male (57.7%), with an average age of 30.3 years. Most subjects (76.8%) were moderately aware of good industrial hygiene practices. SChE level was divided into four groups based on the results. Only 4.4% had normal levels of cholinesterase activity, 20.5% had slightly reduced levels, 58.5% had markedly reduced levels and were "at risk," and 16.6% who had highest levels of cholinesterase inhibition were deemed to be in an "unsafe" range. SChE was classified into two groups, SChE value of 87.5 was "normal" and <87.5 units/mL "abnormal." For the multiple logistic regression analysis of the abnormal SChE levels, the variables entered in the model included gender, period of insecticide use, the total area of plantation, frequency of spraying, period of daily insecticide spraying, and insecticide spraying method. The results indicated that the aOR (adjust odds ratio) for male migrant farm workers (95% confidence interval [CI]) was 1.58 (1.14, 2.17). The OR for farm migrant workers who worked on larger plantations of more than 39.5 acres (95% CI) was 2.69 (1.51, 4.82). Finally, the OR for the migrant farm workers who used a backpack sprayer (95% CI) was 2.07 (1.28, 3.34). These results suggest that health screening should be provided to migrant farm workers, especially those who spray pesticides on plantations of >39 acres, use a backpack sprayer, or have a low level of compliance with accepted industrial hygiene practices. These three classes of workers are at increased risk of chemical exposures and developing acute or chronic illness from pesticide exposures.

  12. The influence of cholinesterase inhibitor therapy for dementia on risk of cardiac pacemaker insertion: a retrospective, population-based, health administrative databases study in Ontario, Canada.

    PubMed

    Huang, Allen R; Redpath, Calum J; van Walraven, Carl

    2015-04-28

    Cholinesterase inhibitors are used to treat the symptoms of dementia and can theoretically cause bradycardia. Previous studies suggest that patients taking these medications have an increased risk of undergoing pacemaker insertion. Since these drugs have a marginal impact on patient outcomes, it might be preferable to change drug treatment rather than implant a pacemaker. This population-based study determined the association of people with dementia exposed to cholinesterase inhibitor medication and pacemaker insertion. We used data from the Ontario health administrative databases from January 1, 1993 to June 30, 2012. We included all community-dwelling seniors who had a code for dementia and were exposed to cholinesterase inhibitors (donezepil, galantamine, and rivastigmine) and/or drugs used to treat co-morbidities of hypertension, diabetes, depression and hypothyroidism. We controlled for exposure to anti-arrhythmic drugs. Observation started at first exposure to any medication and continued until the earliest of pacemaker insertion, death, or end of study. 2,353,909 people were included with 96,000 (4.1%) undergoing pacemaker insertion during the observation period. Case-control analysis showed that pacemaker patients were less likely to be coded with dementia (unadjusted OR 0.42 [95%CI 0.41-0.42]) or exposed to cholinesterase inhibitors (unadjusted OR 0.39 [95%CI 0.37-0.41]). That Cohort analysis showed patients with dementia taking cholinesterase inhibitors had a decreased risk of pacemaker insertion (unadj-HR 0.58 [0.55-0.61]). Adjustment for patient age, sex, and other medications did not notably change results, as did restricting the analysis to incident users. Patients taking cholinesterase inhibitors rarely undergo, and have a significantly reduced risk of, cardiac pacemaker insertion.

  13. Blood cholinesterase levels in a group of Malaysian blood donors.

    PubMed

    Chan, L; Balabaskaran, S; Delilkan, A E; Ong, L H

    1994-12-01

    Data on blood cholinesterase levels in the Malaysian population is lacking. The spectrophotometric method of Ellman was used to determine the red cell, plasma and whole blood cholinesterase (ChE) levels in 407 Malaysian blood donors. The mean+1SD for plasma ChE in females (n = 48) was 2.37 + 0.70 umol/min/ml and 2.76 + 0.75 umol/min/ml in males (n = 359). The mean plasma ChE in males was higher than in females (p < 0.001). The mean+1SD for red cell ChE in females was 9.01 + 1.20 umol/min/ml whereas in males it was 7.69 +1.30 umol/min/ml (the mean red cell ChE in females was higher than in males, p < 0.0001). The mean+1SD for whole blood ChE for females was 4.31+ 0.58 umol/min/ml and for males it was 4.95 + 0.71 umol/min/ml. The mean whole blood ChE in males was higher than in females (p < 0.0001). Sex influenced the plasma, red cell and whole blood ChE. In males the plasma ChE was affected by the race factor. The mean+1SD plasma ChE for the Malay, Chinese and Indian were 2.92 + 0.80, 2.73 + 0.71 and 2.61+ 0.73 respectively (p < 0.002). The age factor in males affected the red cell ChE with 7.88 + 1.32 in the (30-69) age group and 7.47 + 1.23 in the (15-29) age group (p < 0.005). The whole blood ChE in females was affected by blood groups. The mean+1SD whole blood ChE for blood groups A,B and O were 4.19 + 0.42, 3.93 + 0.46 and 4.49 + 0.62 respectively (p < 0.03). The significant difference is between the ChE of group B and O, but the ChE of group A could not be determined to be different from group B or O. These results serve as guidelines for our local population in the evaluation of cholinesterase levels with regard to pesticide poisoning, liver biosynthetic capacity and unusual sensitivity to succinylcholine.

  14. COMPARISON OF ACUTE NEUROBEHAVIORAL AND CHOLINESTERASE INHIBITORY EFFECTS OF N-METHYL CARBAMATES IN RAT

    EPA Science Inventory

    There are few studies evaluating direct functional and biochemical consequences of exposure. In the present study of the acute toxicity of seven N-methyl carbamate pesticides, we evaluated the dose-response profiles of cholinesterase (ChE) inhibition in brain and erythrocytes (R...

  15. Cholinesterase Inhibitory Activity of Some semi-Rigid Spiro Heterocycles: POM Analyses and Crystalline Structure of Pharmacophore Site.

    PubMed

    Hadda, Taibi Ben; Talhi, Oualid; Silva, Artur S M; Senol, Fatma Sezer; Orhan, Ilkay Erdogan; Rauf, Abdur; Mabkhot, Yahia N; Bachari, Khaldoun; Warad, Ismail; Farghaly, Thoraya A; Althagafi, Ismail I; Mubarak, Mohammad S

    2018-01-01

    Cholinesterase family consists of two sister enzymes; acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) which hydrolyze acetylcholine. Since deficit of acetylcholine has been evidenced in patients of Alzheimer's disease (AD), cholinesterase inhibitors are currently the most prescribed drugs for the treatment of AD. our aim in this article was to investigate the inhibitory potential of five known compounds (2-6) with spiro skeleton against AChE and BChE using ELISA microplate assays. In addition to their ChE inhibitory effect, their physico-chemical properties were also calculated. Moreover, the present work aims at investigating the charge/geometrical effect of a hypothetical pharmacophore or bidentate site in a bioactive group, on the inhibition efficiency of spiro compounds 2-6 by using Petra/Osiris/ molinspiration (POM) and X-ray analyses. In the present study, five compounds (2-6) with spiro skeleton have been synthesized and tested in vitro for their inhibitory potential against AChE and BChE using ELISA microtiter plate assays at 25 µg/mL. Results revealed that three of the spiro compounds tested exert more than 50% inhibition against one of cholinesterases. Compound 5 displayed 68.73 ± 4.73% of inhibition toward AChE, whereas compound 6 showed 56.17 ± 0.83% of inhibition toward BChE; these two previously synthesized compounds have been the most active hits. Our data obtained from screening of compounds 2-6 against the two cholinesterases indicate that three of these show good potential to selectively inhibit AChE or BChE. Spiro compounds 2, 5, and 6 exhibited the most potent activity of the series against AChE or BChE with inhibition values in the range 55-70%. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  16. Inhibition of cholinesterases by stereoisomers of Huperzine-A

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Saxena, A.; Qian, N.; Kovach, I.M.

    1993-05-13

    Huperzine-A, a potential drug for the treatment of Alzheimer's disease and possible pretreament for nerve agent toxicity, has recently been characterized as a reversible inhibitor of cholinesterases (Ashani et al., BBRC, 184:719-726, 1992). Long-term incubation of purified cholinesterases with Huperzine-A did not show any chemical modification of Huperzine-A. The dissociation constant, K(I), for fetal bovine serum acetylcholinesterase (FBS AChE) was approximately 20 nM, for Torpedo AChE was 215 nM, and for horse serum butyrylcholinesterase (BChE) was 40 micrometers M. Inhibition studies with the two stereoisomers of Huperzine-A have shown that naturally occurring (-)-Huperzine-A inhibited FBS AChE 35-fold more potently thanmore » (+)-Huperzine-A, with K(I) values of 6.2 nM and 210 nM, respectively. These results are in agreement with those reported previously using crude preparations of rat cortical AChE (McKinney et al., Eur. J. Pharmacol., 203, 303-305, 1991). (-)-Huperzine-A, on the other hand, was 80-fold more potent than (+)-Huperzine-A in inhibiting Torpedo AChE, with K(I), values of 0.25 micrometers M and 22 micrometer M, respectively. No significant differences in K(I) were observed for the two stereoisomers of Huperzine-A with horse serum BChE, indicating the lack of stereoselectivity of this compound for BChE. Molecular modeling studies involving docking of each of the two stereoisomers of Huperzine-A into the active-site gorge of Torpedo AChE also revealed that (-)-Huperzine-A gave a better fit than (+)-Huperzine-A.« less

  17. Prolonged apnoea after suxamethonium: an analysis of the first 225 cases reported to the Danish Cholinesterase Research Unit.

    PubMed

    Viby-Mogensen, J; Hanel, H K

    1978-01-01

    During the last 4 years, 225 patients have been referred to the Danish Cholinesterase Research Unit following an episode of prolonged apnoea after suxamethonium. Fourteen patients (6.2%) were found to have a low serum cholinesterase activity due to an acquired deficiency (for instance, liver disease, chronic debilitating disease or carcinoma). One hundred and forty-eight patients (65.8%) had an inherited abnormal serum cholinesterase, and 105 of these patients (46.7%) were homozygous for the atypical enzyme (E1 Ea1). The mean period of apnoea in this latter group was 92 min (range: 25--240). Seventeen patients (7.6%) were heterozygous for the normal and the atypical enzyme (Eu1 Ea1), with a mean apnoea period of 25 min (range: 7--60 min). Twelve patients were found to be heterozygous for the atypical and the silent gene (E(a)1 E(s)1). The mean period of apnoea was 126 min (range: 45--210 min). Fourteen patients had other rare genotypes. The longest mean period of apnoea (170 min, range: 70--330) was found in patients homozygous for the silent gene (Es1 Es1). The silent gene and the fluoride-resistant gene were found in 8.9% and 2.7% of the patients, respectively. In 63 patients (28.1%) both the type and quantity of serum cholinesterase were normal. In 34 of these patients (15.2%), the prolonged apnoea was due to other causes; for example, suxamethonium overdose, hyperventilation and central as well as peripheral respiratory depression. However, in the other 29 patients (12.9%), the reason for the prolonged apnoea could not be established. The possibility therefore exists that these cases represent unknown genotypes.

  18. An improved radiosynthesis of O-(2-[18 F]fluoroethyl)-O-(p-nitrophenyl)methylphosphonate: A first-in-class cholinesterase PET tracer.

    PubMed

    Neumann, Kiel D; Thompson, Charles M; Blecha, Joseph E; Gerdes, John M; VanBrocklin, Henry F

    2017-06-15

    O-(2-Fluoroethyl)-O-(p-nitrophenyl) methylphosphonate 1 is an organophosphate cholinesterase inhibitor that creates a phosphonyl-serine covalent adduct at the enzyme active site blocking cholinesterase activity in vivo. The corresponding radiolabeled O-(2-[ 18 F]fluoroethyl)-O-(p-nitrophenyl) methylphosphonate, [ 18 F]1, has been previously prepared and found to be an excellent positron emission tomography imaging tracer for assessment of cholinesterases in live brain, peripheral tissues, and blood. However, the previously reported [ 18 F]1 tracer synthesis was slow even with microwave acceleration, required high-performance liquid chromatography separation of the tracer from impurities, and gave less optimal radiochemical yields. In this paper, we report a new synthetic approach to circumvent these shortcomings that is reliant on the facile reactivity of bis-(O,O-p-nitrophenyl) methylphosphonate, 2, with 2-fluoroethanol in the presence of DBU. The cold synthesis was successfully translated to provide a more robust radiosynthesis. Using this new strategy, the desired tracer, [ 18 F]1, was obtained in a non-decay-corrected radiochemical yield of 8 ± 2% (n = 7) in >99% radiochemical and >95% chemical purity with a specific activity of 3174 ± 345 Ci/mmol (EOS). This new facile radiosynthesis routinely affords highly pure quantities of [ 18 F]1, which will further enable tracer development of OP cholinesterase inhibitors and their evaluation in vivo. Copyright © 2017 John Wiley & Sons, Ltd.

  19. Caregiver Acceptance of Adverse Effects and Use of Cholinesterase Inhibitors in Alzheimer's Disease

    ERIC Educational Resources Information Center

    Oremus, Mark; Wolfson, Christina; Vandal, Alain C.; Bergman, Howard; Xie, Qihao

    2007-01-01

    Caregivers play a determining role in choosing treatments for persons with Alzheimer's disease. The objective of this study was to examine caregivers' willingness to have persons with Alzheimer's disease continue taking cholinesterase inhibitors in the event that any 1 of 11 adverse effects was to occur. Data were gathered via postal questionnaire…

  20. Measurement of the affinity and phosphorylation constants governing irreversible inhibition of cholinesterases by di-isopropyl phosphorofluoridate

    PubMed Central

    Main, A. R.; Iverson, F.

    1966-01-01

    1. A procedure is described for determining the affinity constant Ka and the phosphorylation constant kp for the inhibition by di-isopropyl phosphorofluoridate of erythrocyte acetylcholinesterase and serum cholinesterase. The procedure depends on the use of a specially designed reaction vessel with which incubation times as short as 1·2sec. could be obtained at any convenient temperature. 2. The Ka of acetylcholinesterase decreased from 1·58 (±0·22)×10−3m at 5° to 1·17 (±0·10)×10−3m at 25° and the associated change in enthalpy was 2980 cal. 3. The kp of acetylcholinesterase increased from 11·9 (±0·7)min.−1 at 5° to 40·7 (±1·4)min.−1 at 25°, indicating an activational energy of 9600 cal. The change in entropy associated with Ka was 23·5 cal. degree−1 at 25°. 4. At 5°, the Ka and kp of serum cholinesterase were 9·95 (±1·10)×10−6m and 11·2 (±0·63)min.−1 respectively. 5. The 150-fold difference in the inhibitory power of di-isopropyl phosphorofluoridate for the two cholinesterases was attributed entirely to differences in affinity. PMID:5968549

  1. Novel cholinesterase modulators and their ability to interact with DNA

    NASA Astrophysics Data System (ADS)

    Janockova, Jana; Gulasova, Zuzana; Musilek, Kamil; Kuca, Kamil; Kozurkova, Maria

    2013-11-01

    In the present work, an interaction of four cholinesterase modulators (1-4) with calf thymus DNA was studied via spectroscopic techniques (UV-Vis, fluorescent spectroscopy and circular dichroism). From UV-Vis spectroscopic analysis, the binding constants for DNA-pyridinium oximes complexes were calculated (K = 3.5 × 104 to 1.4 × 105 M-1). All these measurements indicated that the compounds behave as effective DNA-interacting agents. Electrophoretic techniques proved that ligand 2 inhibited topoisomerase I at a concentration 5 μM.

  2. Novel N-allyl/propargyl tetrahydroquinolines: Synthesis via Three-component Cationic Imino Diels-Alder Reaction, Binding Prediction, and Evaluation as Cholinesterase Inhibitors.

    PubMed

    Rodríguez, Yeray A; Gutiérrez, Margarita; Ramírez, David; Alzate-Morales, Jans; Bernal, Cristian C; Güiza, Fausto M; Romero Bohórquez, Arnold R

    2016-10-01

    New N-allyl/propargyl 4-substituted 1,2,3,4-tetrahydroquinolines derivatives were efficiently synthesized using acid-catalyzed three components cationic imino Diels-Alder reaction (70-95%). All compounds were tested in vitro as dual acetylcholinesterase and butyryl-cholinesterase inhibitors and their potential binding modes, and affinity, were predicted by molecular docking and binding free energy calculations (∆G) respectively. The compound 4af (IC50 = 72 μm) presented the most effective inhibition against acetylcholinesterase despite its poor selectivity (SI = 2), while the best inhibitory activity on butyryl-cholinesterase was exhibited by compound 4ae (IC50 = 25.58 μm) with considerable selectivity (SI = 0.15). Molecular docking studies indicated that the most active compounds fit in the reported acetylcholinesterase and butyryl-cholinesterase active sites. Moreover, our computational data indicated a high correlation between the calculated ∆G and the experimental activity values in both targets. © 2016 The Authors Chemical Biology & Drug Design Published by John Wiley & Sons Ltd.

  3. DIFFERENTIAL PROFILES OF CHOLINESTERASE INHIBITION AND NEUROBEHAVIORAL EFFECTS IN RATS EXPOSED TO FENAMIPHOS AND PROFENOPHOS.

    EPA Science Inventory

    The relationship between cholinesterase (ChE) inhibition and neurobehavioral changes was examined using two ChE-inhibiting organophosphorus pesticides, fenamiphos and profenophos. Both pesticides inhibit blood ChE, yet brain ChE is relatively spared (little to no inhibition up t...

  4. BEHAVIORAL AND NEUROCHEMICAL EFFECTS OF ACUTE CHLORPYRIFOS IN RATS: TOLERANCE TO PROLONGED INHIBITION OF CHOLINESTERASE

    EPA Science Inventory

    Chlorpyrifos (CPF), a commercially prevalent organophosphate (OP) pesticide, inhibits blood and brain cholinesterase for up to 10 weeks after acute s.c. injection in rats. his prolonged inhibition suggested that acute CPF may affect muscarinic receptors and behavior as does repea...

  5. Spatiotemporal relationship of embryonic cholinesterases with cell proliferation in chicken brain and eye.

    PubMed Central

    Layer, P G; Sporns, O

    1987-01-01

    Close relationships between acetylcholinesterase (AcChoEase; acetylcholine acetylhydrolase, true cholinesterase, EC, 3.1.1.7) and butyrylcholinesterase (BtChoEase, acylcholine acylhydrolase, pseudocholinesterase, EC, 3.1.1.8) with cell proliferation were observed in the early chicken brain. These include the following: BtChoEase is transiently accumulating in patchy fashion on the ventricular side of the neuroepithelium shortly before AcChoEase appears in cell bodies along the opposing mantle layer. The amount of BtChoEase in retina and brain is greatest in the early phase (E3-E5, or incubation periods of 3-5 days); in retina it decreases about 2 days later than in brain. However, AcChoEase expression increases with time, in inverse order to that of BtChoEase. In both tissues decrease of cell proliferation is closely followed by decrease in BtChoEase. A double-labeling technique of cholinesterase staining together with [3H]thymidine autoradiography reveals proliferation zones that are diffusely stained by BtChoEase but not by AcChoEase. Patches intensely stained for BtChoEase accompany clusters of cells in final stages of mitosis on their way to the differentiation zone, where they begin expressing AcChoEase. By applying different thymidine pulses, we identify an 11-hr lag from the last thymidine-uptake to full AcChoEase expression. (iv) These findings are confirmed by studying lens development, where areas of proliferation and differentiation are well separated. The spatiotemporal pattern of the transition of neuroblasts from a proliferating into a differentiating state correlates with the expression of BtChoEase just before and during mitosis and that of AcChoEase about 11 hr after mitosis. Thus cholinesterases could be involved in the regulation of this transition. Images PMID:3467355

  6. Brain cholinesterase inhibition in songbirds from pecan groves sprayed with phosaline and disulfoton

    USGS Publications Warehouse

    White, D.H.; Seginak, J.T.

    1990-01-01

    Disulfoton at 0.83 kg/ha caused moderate to severe brain cholinesterase (ChE) depression in 11 of 15 blue jays collected in pecan groves 6-7 hr after the application. Phosalone at 0.83 kg/ha to pecan groves caused only slight ChE inhibition in a few blue jays and red-bellied woodpeckers.

  7. New Carrier Made from Glass Nanofibres for the Colorimetric Biosensor of Cholinesterase Inhibitors.

    PubMed

    Matějovský, Lukáš; Pitschmann, Vladimír

    2018-05-30

    Cholinesterase inhibitors are widely used as pesticides in agriculture, but also form a group of organophosphates known as nerve chemical warfare agents. This calls for close attention regarding their detection, including the use of various biosensors. One such biosensor made in the Czech Republic is the Detehit, which is based on a cholinesterase reaction that is assessed using a colour indicator-the Ellman's reagent-which is anchored on cellulose filter paper together with the substrate. With the use of this biosensor, detection is simple, quick, and sensitive. However, its disadvantage is that a less pronounced yellow discoloration occurs, especially under difficult light conditions. As a possible solution, a new indicator/substrate carrier has been designed. It is made of glass nanofibres, so the physical characteristics of the carrier positively influence reaction conditions, and as a result improve the colour response of the biosensor. The authors present and discuss some of the results of the study of this carrier under various experimental conditions. These findings have been used for the development of a modified Detehit biosensor.

  8. Antioxidant and cholinesterase inhibitory activity of a new peptide from Ziziphus jujuba fruits.

    PubMed

    Zare-Zardini, Hadi; Tolueinia, Behnaz; Hashemi, Azam; Ebrahimi, Leila; Fesahat, Farzaneh

    2013-11-01

    Antioxidant agents and cholinesterase inhibitors are the foremost drugs for the treatment of Alzheimer's disease (AD). In this study, a new peptide from Ziziphus jujuba fruits was investigated for its inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes as well as antioxidant activity. This peptide was introduced as a new peptide and named Snakin-Z. The Snakin-Z displayed considerable cholinesterase inhibition against AChE and BChE. The half maximal inhibitory concentration (IC50) values of Snakin-Z against AChE and BChE are 0.58 ± 0.08 and 0.72 ± 0.085 mg/mL, respectively. This peptide has 80% enzyme inhibitory activity on AChE and BChE at 1.5 mg/mL. The Snakin-Z also had the high antioxidant activity (IC50 = 0.75 ± 0.09 mg/mL). Thus, it is suggested that Snakin-Z may be beneficial in the treatment of AD. However, more detailed researches are still required as in vivo testing its anticholinesterase and antioxidant activities.

  9. New Indole Alkaloids from the Bark of Rauvolfia Reflexa and their Cholinesterase Inhibitory Activity.

    PubMed

    Fadaeinasab, Mehran; Basiri, Alireza; Kia, Yalda; Karimian, Hamed; Ali, Hapipah Mohd; Murugaiyah, Vikneswaran

    2015-01-01

    Rauvolfia reflexa is a member of the Apocynaceae family. Plants from the Apocynaceae family have been traditionally used in the treatment of age-related brain disorders Methods and Results: Two new indole alkaloids, rauvolfine C (1) and 3-methyl-10,11-dimethoxy-6-methoxycarbonyl-β-carboline (2), along with five known, macusine B (3), vinorine (4), undulifoline (5), isoresrpiline (6) and rescinnamine (7) were isolated from the bark of Rauvolfia reflexa. Cholinesterase inhibitory assay and molecular docking were performed to get insight of the inhibitory activity and molecular interactions of the compounds. The compounds showed good to moderate cholinesterase inhibitory activity with IC50 values in the range of 8.06 to 73.23 µM. Compound 7 was found to be the most potent inhibitor of both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Compounds 1, 2, 5 and 6 were found to be selective towards BChE, while compounds 3, 4 and 7 were dual inhibitors, having almost equal inhibitory activity on both AChE and BChE. Molecular docking revealed that compounds 6 and 7 interacted differently on AChE and BChE, by means of hydrophobic interactions and hydrogen bonding. In AChE, the indole moiety of both compounds interacted with the residues lining the peripheral anionic site, whereas in BChE, their methoxy groups are primarily responsible for the strong inhibitory activity via interactions with residues at the active site of the enzyme. Two new and five known indole alkaloids were isolated from R. reflexa. Among the compounds, 7 and 6 showed the most potent and promising cholinesterase inhibitory activity, worthy for further investigations. © 2015 S. Karger AG, Basel.

  10. Quantitative distributions of different cholinesterases and inhibition of acetylcholinesterase by metidathion and paraquat in alimentary canal of common carp.

    PubMed

    Láng, G; Kufcsák, O; Szegletes, T; Nemcsók, J

    1997-07-01

    1. The cholinesterases play an important role in the innervation of organs. The ratio of solubilized to membrane-bound cholinesterase and the quantitative distributions of acetylcholinesterase and butyrylcholinesterase were measured in different segments of the gut of carp (Cyprinus carpio) connected with different types of nerve-muscle synapses in different parts of the alimentary tract. 2. The inhibition of acetylcholinesterase (EC 3.1.1.7.) by the herbicide paraquat and the insecticide metidathion was measured in different parts of the gut of carp. 3. Metidathion and paraquat significantly decreased the activity of acetylcholinesterase in different segments of the alimentary tract of common carp, in a concentration-dependent manner.

  11. Preparation and evaluation of carriers for detection of cholinesterase inhibitors.

    PubMed

    Vetchý, David; Pitschmann, Vladimír; Vetchá, Martina; Kašparovský, Tomáš; Matějovský, Lukáš

    2015-01-01

    The aim of the study was to use methods of pharmaceutical technology, and prepare carriers in the form of pellets suitable as a filling of detection tubes for enzymatic detection of cholinesterase inhibitors. The enzymatic detection was based on enzymatic hydrolysis of acetylthiocholine iodide and the subsequent colour reaction of its hydrolysis product with Ellman's reagent. The suitable carriers should be in the form of white, regular and sufficiently mechanically resistant particles of about 1 mm allowing it to capture the enzyme during the impregnation process and ensuring its high activity for enzymatic detection. Carriers consisting of microcrystalline cellulose, lactose, povidone, and sodium carboxymethyl cellulose were prepared using extrusion-spheronization method under three different drying conditions in either a hot air oven or a microwave oven. Subsequently, the carriers were impregnated with acetylcholinesterase and their size, shape, mechanical resistance, bulk, tapped and pycnometric density, Hausner ratio, intraparticular and total tapped porosity, and activity were measured and recorded. In this procedure, carriers with different physical parameters and different acetylcholinesterase activity were evaluated. It was found that higher acetylcholinesterase activity was associated not only with a higher intraparticular porosity but also with more regular particles characterized by high sphericity and low total tapped porosity. This unique finding is important for the preparation of detection tubes based on enzymatic detection which is still irreplaceable especially in the field of detection and analysis of super-toxic cholinesterase inhibitors.

  12. Arylesterase Phenotype-Specific Positive Association Between Arylesterase Activity and Cholinesterase Specific Activity in Human Serum

    PubMed Central

    Aoki, Yutaka; Helzlsouer, Kathy J.; Strickland, Paul T.

    2014-01-01

    Context: Cholinesterase (ChE) specific activity is the ratio of ChE activity to ChE mass and, as a biomarker of exposure to cholinesterase inhibitors, has a potential advantage over simple ChE activity. Objective: To examine the association of several potential correlates (serum arylesterase/paraoxonase activity, serum albumin, sex, age, month of blood collection, and smoking) with plasma ChE specific activity. Methods: We analyzed data from 195 cancer-free controls from a nested case-control study, accounting for potential confounding. Results: Arylesterase activity had an independent, statistically significant positive association with ChE specific activity, and its magnitude was the greatest for the arylesterase phenotype corresponding to the QQ PON1192 genotype followed by phenotypes corresponding to QR and RR genotypes. Serum albumin was positively associated with ChE specific activity. Conclusions: Plasma arylesterase activity was positively associated with plasma ChE specific activity. This observation is consistent with protection conferred by a metabolic phenotype resulting in reduced internal dose. PMID:24473115

  13. Characterization and in vitro sensitivity of cholinesterases of gilthead seabream (Sparus aurata) to organophosphate pesticides.

    PubMed

    Albendín, G; Arellano, J M; Mánuel-Vez, M P; Sarasquete, C; Arufe, M I

    2017-04-01

    The characterization of cholinesterase activity in brain and muscle of gilthead seabream was carried out using four specific substrates and three selective inhibitors. In addition, K m and V max were calculated from the Michaelis-Menten equation for ASCh and BSCh substrates. Finally, the in vitro sensitivity of brain and muscle cholinesterases to three organophosphates (OPs) was also investigated by estimating inhibition kinetics. The results indicate that AChE is the enzyme present in the brain, whereas in muscle, a typical AChE form is present along with an atypical form of BChE. Very low ChE activity was found in plasma with all substrates used. The inhibitory potency of the studied OPs on brain and muscle AChEs based on bimolecular inhibition constants (k i ) was: omethoate < dichlorvos < azinphosmethyl-oxon. Furthermore, muscle BChE was found to be several orders of magnitude (from 2 to 4) more sensitive than brain and muscle AChE inhibition by dichlorvos and omethoate.

  14. Variation in plasma cholinesterase activity among greenhouse workers, fruitgrowers, and slaughtermen.

    PubMed Central

    Lander, F; Lings, S

    1991-01-01

    The purpose of the study was to compare the plasma cholinesterase (ChE) activities of 100 greenhouse workers and 43 fruitgrowers engaged in spraying insecticides with those of 113 slaughtermen who served as controls. The ChE activity in the greenhouse workers and fruitgrowers was not significantly lower than in the controls. Nevertheless the ChE activity of greenhouse workers declined with increasing exposure. The wearing of protective gloves appears to be of particular value for the safety of workers. PMID:2015206

  15. Chemical and molecular aspects on interactions of galanthamine and its derivatives with cholinesterases.

    PubMed

    Gulcan, Hayrettin O; Orhan, Ilkay E; Sener, Bilge

    2015-01-01

    Dual action of galanthamine as potent cholinesterase inhibitor and nicotinic modulator has attracted a great attention to be used in the treatment of AD. Consequently, galanthamine, a natural alkaloid isolated from a Galanthus species (snowdrop, Amaryllidaceae), has become an attractive model compound for synthesis of its novel derivatives to discover new drug candidates. Numerous studies have been done to elucidate interactions between galanthamine and its different derivatives and the enzymes; acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) using in vitro and in silico experimental models. The in vitro studies revealed that galanthamine inhibits AChE in strong, competitive, long-acting, and reversible manner as well as BChE, although its selectivity towards AChE is much higher than BChE. The in silico studies carried out by employing molecular docking experiments as well as molecular dynamics simulations pointed out to existence of strong interactions of galanthamine with the active gorge of AChE, mostly of Torpedo californica (the Pasific electric ray) origin. In this review, we evaluate the mainstays of cholinesterase inhibitory action of galanthamine and its various derivatives from the point of view of chemical and molecular aspects.

  16. Cholinesterase Confabs and Cousins: Approaching Forty Years

    PubMed Central

    Taylor, Palmer; De Jaco, Antonella; Comoletti, Davide; Miller, Meghan; Camp, Shelley

    2013-01-01

    In the past four decades of cholinesterase (ChE) research, we have seen substantive evolution of the field from one centered around substrate and inhibitor kinetic profiles and compound characterizations to the analysis of ChE structure, first through the gene families and then by x-ray crystallographic determinations of the free enzymes and their complexes and conjugates. Indeed, these endeavors have been facilitated by recombinant DNA technologies, structure determinations and parallel studies in related proteins in the α/β-hydrolase fold family. This approach has not only contributed to a fundamental understanding of structure and function of a large family of hydrolase-like proteins possessing functions other than catalysis, but also has been used to develop new practical strategies for scavenging and antidotal activity in cases of organophosphate insecticide or nerve agent exposure. PMID:23085121

  17. CHANGES OF CHOLINESTERASE IN THE BLOOD AND TISSUES OF RATS SUBJECTED TO IONIZING RADIATION (in Italian)

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Tominz, L.; Andri, L.; Caprotti, M.

    1963-03-01

    Cholinesterase activity in blood and in liver, kidney, and brain homogenates of rats subjected to sublethal doses of ionizing radiation was studied. Male rats ( approximates 250 g) were divided into groups, of which the control group numbered 12. Another group (13 animals) was sacrificed 3 hr after total irradiation (230 kv; 12 ma; filter 1 mm Cu, 1 mm Al; total dose 600 r); a third group was sacrificed 24 hr after total irradiation. Cholinesterase activity was measured by the method of Salvini and Tominz and of Tominz and Cazzaniga; results, expressed in mu moles NaOH consumed in 1more » min by 1 ml blood or 1 g tissue, were as follows for controls, 3-hr animals, and 24-hr animals: liver, 3.84 plus or minus 0.33, 4.11 plus or minus 0.19,4.13 plus or minus 0.16; kidneys, 2.06 plus or minus 0.27, 1.9 plus or minus 0.20, 1.8 plus or minus 0.09; brain, 8.7 plus or minus 1.5, 9.8 plus or minus 0.56, 9.19 plus or minus 1.2; total blood, 0.882 plus or minus 0.164, 0.884 plus or minus 0.031, 0.715 plus or minus 0.024. Thus, significant variations in tissue cholinesterase do not appear on total irradiation; on the other hand total blood activity drops by 23% at the third hr and 20% at the 24th. (BBB)« less

  18. [Reference values for erythrocyte cholinesterase activity in the working population of Antioquia, Colombia, according to the Michel and EQM techniques].

    PubMed

    Carmona-Fonseca, Jaime

    2003-11-01

    To establish reference values for erythrocyte cholinesterase (EC 3.1.1.7) activity for the active working population of two regions of the department of Antioquia, Colombia, that are located at different altitudes above sea level. We took representative samples from populations of active working persons 18 to 59 years old from two regions in the department of Antioquia: (1) the Aburrá Valley (1 540 m above sea level) and (2) the near east of the department (2 150 m above sea level). We excluded workers who were using cholinesterase-inhibiting substances in their work or at home, those who had a disease that altered their cholinesterase levels, and those who said they were not in good health. We measured the erythrocyte cholinesterase activity using two methods: (1) the Michel method and (2) the EQM method (EQM Research, Cincinnati, Ohio, United States of America). We carried out the measurements with 827 people, 415 from the Aburrá Valley and 412 from the near east region. We compared proportions using the chi-square test and Fisher's exact test. We utilized the Student's t test for independent samples to compare two averages. To simultaneously compare three or more averages, analysis of variance was used, followed by the Newman-Keuls multiple-range test. When the variables were not normally distributed or when the variances were not homogeneous, Kruskal-Wallis nonparametric analysis of variance was used to compare the medians. Three computer software programs were used in the statistical analysis: SPSS 9.0, SGPlus 7.1, and Epi Info 6.04. In all the statistical tests the level of significance was set at P < 0.05. The average erythrocyte cholinesterase activity value that we found for the studied population by using the Michel method was 0.857 delta pH/hour (95% confidence interval (CI): 0.849 to 0.866), and the average value found through the EQM method was 35.21 U/g hemoglobin (95% CI: 34.82 to 35.60). With the Michel method: (1) the enzymatic activity differed

  19. Potentiation of a functional autoantibody in narcolepsy by a cholinesterase inhibitor.

    PubMed

    Jackson, Michael W; Spencer, Nicolas J; Reed, Joanne H; Smith, Anthony J F; Gordon, Tom P

    2009-12-01

    We have recently reported the presence of an immunoglobulin G (IgG) autoantibody (Ab) in patients with narcolepsy with cataplexy that abolishes spontaneous colonic migrating motor complexes (CMMCs) and increases smooth muscle tension and atropine-sensitive phasic contractions in a physiological assay of an isolated colon. In this study, we used the cholinesterase inhibitor, neostigmine, to explore the mechanism of the narcoleptic IgG-mediated disruption of enteric motor function in four patients with narcolepsy with cataplexy and to identify a pharmacological mimic of the Ab. Neostigmine potentiated the narcoleptic IgG-mediated increase in smooth muscle resting tension and phasic smooth muscle contractions by an atropine-sensitive mechanism but exerted no effect on resting tension in the presence of control IgG. Decreased frequency of CMMCs mediated by IgG with anti-M3R activity was reversed by neostigmine. Therefore, a challenge with a cholinesterase inhibitor improves the specificity of the CMMC assay for narcoleptic IgG. Tetrodotoxin (TTX), a neuronal sodium channel blocker, also abolished CMMCs and increased resting tone, and a similar potentiation was observed with neostigmine; thus, TTX is a mimic of the functional effects of the narcoleptic IgG in this bioassay. These findings provide a link to pharmacological studies of canine narcolepsy and are consistent with a functional blockade of both excitatory and inhibitory motor neurons by the narcoleptic Ab, similar to the TTX mimic, presumably by binding to an autoantigenic target expressed in both populations of neurons.

  20. Design, synthesis and evaluation of novel cinnamic acid derivatives bearing N-benzyl pyridinium moiety as multifunctional cholinesterase inhibitors for Alzheimer's disease.

    PubMed

    Lan, Jin-Shuai; Hou, Jian-Wei; Liu, Yun; Ding, Yue; Zhang, Yong; Li, Ling; Zhang, Tong

    2017-12-01

    A novel family of cinnamic acid derivatives has been developed to be multifunctional cholinesterase inhibitors against AD by fusing N-benzyl pyridinium moiety and different substituted cinnamic acids. In vitro studies showed that most compounds were endowed with a noteworthy ability to inhibit cholinesterase, self-induced Aβ (1-42) aggregation, and to chelate metal ions. Especially, compound 5l showed potent cholinesterase inhibitory activity (IC 50 , 12.1 nM for eeAChE, 8.6 nM for hAChE, 2.6 μM for eqBuChE and 4.4 μM for hBuChE) and the highest selectivity toward AChE over BuChE. It also showed good inhibition of Aβ (1-42) aggregation (64.7% at 20 μM) and good neuroprotection on PC12 cells against amyloid-induced cell toxicity. Finally, compound 5l could penetrate the BBB, as forecasted by the PAMPA-BBB assay and proved in OF1 mice by ex vivo experiments. Overall, compound 5l seems to be a promising lead compound for the treatment of Alzheimer's diseases.

  1. Studies on combined effects of organophosphates or carbamates and morsodren in birds. II. Plasma and cholinesterase in quail fed morsodren and orally dosed with parathion or carbofuran

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Dieter, M.P.; Ludke, J.L.

    1978-04-01

    The degree of interaction between mercury and cholinesterase inhibiting pesticides was determined by comparing enzyme responses to sublethal dosages of parathion or carbofuran in quail fed 0.05, 0.5, or 5.0 ppM morsodren for 18 weeks. A statistically significant interaction was defined as greater brain cholinesterase inhibition in morsodren-fed than in clean-fed birds following pesticide dosage. The tissue residues of mercury that accumulated before significant mercury-parathion interactions occurred were higher than levels that might be expected in natural populations, but significant mercury-carbofuran interactions occurred in birds that had only accumulated 1.0 ppM liver mercury. The results indicate that indiscriminate usage ofmore » cholinesterase inhibiting pesticides is dangerous, since natural populations of fish-eating birds oftentimes contain this magnitude of mercury.« less

  2. Cholinesterase inhibitors from the roots of Harpagophytum procumbens.

    PubMed

    Bae, Yoon Ho; Cuong, To Dao; Hung, Tran Manh; Kim, Jeong Ah; Woo, Mi Hee; Byeon, Jeong Su; Choi, Jae Sue; Min, Byung Sun

    2014-01-01

    Inhibition of cholinesterase has been proposed to be a therapeutic target for the treatment of Alzheimer's diseases. In our preliminary screening study on the acetylcholinesterase (AChE) inhibitory activity, an ethyl acetate soluble fraction of the roots of Harpagophytum procumbens (Pedaliaceae) was found to inhibit AChE activity at the concentration of 100 μg/mL. Ten compounds (1-10) were isolated from the active fraction and evaluated for their inhibitory effect on AChE and butyrylcholinesterase (BChE). Among the isolates, verbascosides (5, 6, and 8) containing a caffeoyl and a 3,4-dihydroxyphenethyl groups in their structures, showed effective AChE inhibitory activity and also possessed BChE inhibitory activity. The findings suggest that verbascoside derivatives may be partially related to the anti-Alzheimer effect of this medicinal plant.

  3. Multitarget-directed tricyclic pyridazinones as G protein-coupled receptor ligands and cholinesterase inhibitors.

    PubMed

    Pau, Amedeo; Catto, Marco; Pinna, Giovanni; Frau, Simona; Murineddu, Gabriele; Asproni, Battistina; Curzu, Maria M; Pisani, Leonardo; Leonetti, Francesco; Loza, Maria Isabel; Brea, José; Pinna, Gérard A; Carotti, Angelo

    2015-06-01

    By following a multitarget ligand design approach, a library of 47 compounds was prepared, and they were tested as binders of selected G protein-coupled receptors (GPCRs) and inhibitors of acetyl and/or butyryl cholinesterase. The newly designed ligands feature pyridazinone-based tricyclic scaffolds connected through alkyl chains of variable length to proper amine moieties (e.g., substituted piperazines or piperidines) for GPCR and cholinesterase (ChE) molecular recognition. The compounds were tested at three different GPCRs, namely serotoninergic 5-HT1A, adrenergic α1A, and dopaminergic D2 receptors. Our main goal was the discovery of compounds that exhibit, in addition to ChE inhibition, antagonist activity at 5-HT1A because of its involvement in neuronal deficits typical of Alzheimer's and other neurodegenerative diseases. Ligands with nanomolar affinity for the tested GPCRs were discovered, but most of them behaved as dual antagonists of α1A and 5-HT1A receptors. Nevertheless, several compounds displaying this GPCR affinity profile also showed moderate to good inhibition of AChE and BChE, thus deserving further investigations to exploit the therapeutic potential of such unusual biological profiles. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  4. Sesquiterpene Lactones from Cynara cornigera: Acetyl Cholinesterase Inhibition and In Silico Ligand Docking.

    PubMed

    Hegazy, Mohamed-Elamir F; Ibrahim, Abeer Y; Mohamed, Tarik A; Shahat, Abdelaaty A; El Halawany, Ali M; Abdel-Azim, Nahla S; Alsaid, Mansour S; Paré, Paul W

    2016-01-01

    Wild artichoke (Cynara cornigera), a thistle-like perennial belonging to the Asteraceae family, is native to the Mediterranean region, northwestern Africa, and the Canary Islands. While the pleasant, albeit bitter, taste of the leaves and flowers is attributed to the sesquiterpene lactones cynaropicrin and cynarin, a comprehensive phytochemical investigation still needs to be reported. In this study seven sesquiterpene lactones were isolated from an aqueous methanol plant extract, including a new halogenated metabolite (1), the naturally isolated compound sibthorpine (2), and five metabolites isolated for the first time from C. cornigera. Structures were established by spectroscopic methods, including HREIMS, (1 )H, (13 )C, DEPT, (1 )H-(1 )H COSY, HMQC, and HMBC-NMR experiments as well as by X-ray analysis. The isolated bioactive nutrients were analyzed for their antioxidant and metal chelating activity. Compound 1 exhibited a potent metal chelating activity as well as a high antioxidant capacity. Moreover, select compounds were effective as acetyl cholinesterase inhibitors presenting the possibility for such compounds to be examined for anti-neurodegenerative activity. A computational pharmacophore elucidation and docking study was performed to estimate the pharmacophoric features and binding conformation of isolated compounds in the acetyl cholinesterase active site. Georg Thieme Verlag KG Stuttgart · New York.

  5. Evaluation of Antioxidant, Anti-cholinesterase, and Anti-inflammatory Effects of Culinary Mushroom Pleurotus pulmonarius.

    PubMed

    Nguyen, Trung Kien; Im, Kyung Hoan; Choi, Jaehyuk; Shin, Pyung Gyun; Lee, Tae Soo

    2016-12-01

    Culinary mushroom Pleurotus pulmonarius has been popular in Asian countries. In this study, the anti-oxidant, cholinesterase, and inflammation inhibitory activities of methanol extract (ME) of fruiting bodies of P. pulmonarius were evaluted. The 1,1-diphenyl-2-picryl-hydrazy free radical scavenging activity of ME at 2.0 mg/mL was comparable to that of butylated hydroxytoluene, the standard reference. The ME exhibited significantly higher hydroxyl radical scavenging activity than butylated hydroxytoluene. ME showed slightly lower but moderate inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase than galantamine, a standard AChE inhibitor. It also exhibited protective effect against cytotoxicity to PC-12 cells induced by glutamate (10~100 µg/mL), inhibitory effect on nitric oxide (NO) production and inducible nitric oxide synthase protein expression in lipopolysaccharide-stimulated RAW 264.7 macrophages, and carrageenan-induced paw edema in a rat model. High-performance liquid chromatography analysis revealed the ME of P. pulmonarius contained at least 10 phenolic compounds and some of them were identified by the comparison with known standard phenolics. Taken together, our results demonstrate that fruiting bodies of P. pulmonarius possess antioxidant, anti-cholinesterase, and inflammation inhibitory activities.

  6. Evaluation of Antioxidant, Anti-cholinesterase, and Anti-inflammatory Effects of Culinary Mushroom Pleurotus pulmonarius

    PubMed Central

    Nguyen, Trung Kien; Im, Kyung Hoan; Choi, Jaehyuk; Shin, Pyung Gyun

    2016-01-01

    Culinary mushroom Pleurotus pulmonarius has been popular in Asian countries. In this study, the anti-oxidant, cholinesterase, and inflammation inhibitory activities of methanol extract (ME) of fruiting bodies of P. pulmonarius were evaluted. The 1,1-diphenyl-2-picryl-hydrazy free radical scavenging activity of ME at 2.0 mg/mL was comparable to that of butylated hydroxytoluene, the standard reference. The ME exhibited significantly higher hydroxyl radical scavenging activity than butylated hydroxytoluene. ME showed slightly lower but moderate inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase than galantamine, a standard AChE inhibitor. It also exhibited protective effect against cytotoxicity to PC-12 cells induced by glutamate (10~100 µg/mL), inhibitory effect on nitric oxide (NO) production and inducible nitric oxide synthase protein expression in lipopolysaccharide-stimulated RAW 264.7 macrophages, and carrageenan-induced paw edema in a rat model. High-performance liquid chromatography analysis revealed the ME of P. pulmonarius contained at least 10 phenolic compounds and some of them were identified by the comparison with known standard phenolics. Taken together, our results demonstrate that fruiting bodies of P. pulmonarius possess antioxidant, anti-cholinesterase, and inflammation inhibitory activities. PMID:28154487

  7. Different Cholinesterase Inhibitor Effects on CSF Cholinesterases in Alzheimer Patients

    PubMed Central

    Nordberg, Agneta; Darreh-Shori, Taher; Peskind, Elaine; Soininen, Hilkka; Mousavi, Malahat; Eagle, Gina; Lane, Roger

    2014-01-01

    Background The current study aimed to compare the effects of different cholinesterase inhibitors on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities and protein levels, in the cerebrospinal fluid (CSF) of Alzheimer disease (AD) patients. Methods and Findings AD patients aged 50–85 years were randomized to open-label treatment with oral rivastigmine, donepezil or galantamine for 13 weeks. AChE and BuChE activities were assayed by Ellman’s colorimetric method. Protein levels were assessed by enzyme-linked immunosorbent assay (ELISA). Primary analyses were based on the Completer population (randomized patients who completed Week 13 assessments). 63 patients were randomized to treatment. Rivastigmine was associated with decreased AChE activity by 42.6% and decreased AChE protein levels by 9.3%, and decreased BuChE activity by 45.6% and decreased BuChE protein levels by 21.8%. Galantamine decreased AChE activity by 2.1% and BuChE activity by 0.5%, but increased AChE protein levels by 51.2% and BuChE protein levels by10.5%. Donepezil increased AChE and BuChE activities by 11.8% and 2.8%, respectively. Donepezil caused a 215.2%increase in AChE and 0.4% increase in BuChE protein levels. Changes in mean AChE-Readthrough/Synaptic ratios, which might reflect underlying neurodegenerative processes, were 1.4, 0.6, and 0.4 for rivastigmine, donepezil and galantamine, respectively. Conclusion The findings suggest pharmacologically-induced differences between rivastigmine, donepezil and galantamine. Rivastigmine provides sustained inhibition of AChE and BuChE, while donepezil and galantamine do not inhibit BuChE and are associated with increases in CSF AChE protein levels. The clinical implications require evaluation. PMID:19199870

  8. Different cholinesterase inhibitor effects on CSF cholinesterases in Alzheimer patients.

    PubMed

    Nordberg, Agneta; Darreh-Shori, Taher; Peskind, Elaine; Soininen, Hilkka; Mousavi, Malahat; Eagle, Gina; Lane, Roger

    2009-02-01

    The current study aimed to compare the effects of different cholinesterase inhibitors on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities and protein levels, in the cerebrospinal fluid (CSF) of Alzheimer disease (AD) patients. AD patients aged 50-85 years were randomized to open-label treatment with oral rivastigmine, donepezil or galantamine for 13 weeks. AChE and BuChE activities were assayed by Ellman's colorimetric method. Protein levels were assessed by enzyme-linked immunosorbent assay (ELISA). Primary analyses were based on the Completer population (randomized patients who completed Week 13 assessments). 63 patients were randomized to treatment. Rivastigmine was associated with decreased AChE activity by 42.6% and decreased AChE protein levels by 9.3%, and decreased BuChE activity by 45.6% and decreased BuChE protein levels by 21.8%. Galantamine decreased AChE activity by 2.1% and BuChE activity by 0.5%, but increased AChE protein levels by 51.2% and BuChE protein levels by 10.5%. Donepezil increased AChE and BuChE activities by 11.8% and 2.8%, respectively. Donepezil caused a 215.2% increase in AChE and 0.4% increase in BuChE protein levels. Changes in mean AChE-Readthrough/Synaptic ratios, which might reflect underlying neurodegenerative processes, were 1.4, 0.6, and 0.4 for rivastigmine, donepezil and galantamine, respectively. The findings suggest pharmacologically-induced differences between rivastigmine, donepezil and galantamine. Rivastigmine provides sustained inhibition of AChE and BuChE, while donepezil and galantamine do not inhibit BuChE and are associated with increases in CSF AChE protein levels. The clinical implications require evaluation.

  9. Estimation of plasma tacrine concentrations using an in vitro cholinesterase inhibition assay

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Moriearty, P.L.; Kenny, W.; Kumar, V.

    THA (9-amino, 1,2,3,4-tetrahydroacridine; tacrine) is currently under study as a cholinesterase (ChE) inhibitor in Alzheimer disease. In this study, a sensitive radiometric assay for THA inhibition of human plasma ChE, suitable for detection of effects of orally administered drug, is described. The assay is sensitive in a range of 4-50 ng/ml plasma. Reversibility of the inhibition permits distinguishing of drug effects on ChE from changes in amount of enzyme synthesized during treatment.

  10. New pharmacological approaches to the cholinergic system: an overview on muscarinic receptor ligands and cholinesterase inhibitors.

    PubMed

    Greig, Nigel H; Reale, Marcella; Tata, Ada M

    2013-08-01

    The cholinergic system is expressed in neuronal and in non-neuronal tissues. Acetylcholine (ACh), synthesized in and out of the nervous system can locally contribute to modulation of various cell functions (e.g. survival, proliferation). Considering that the cholinergic system and its functions are impaired in a number of disorders, the identification of new pharmacological approaches to regulate cholinergic system components appears of great relevance. The present review focuses on recent pharmacological drugs able to modulate the activity of cholinergic receptors and thereby, cholinergic function, with an emphasis on the muscarinic receptor subtype, and additionally covers the cholinesterases, the main enzymes involved in ACh hydrolysis. The presence and function of muscarinic receptor subtypes both in neuronal and non-neuronal cells has been demonstrated using extensive pharmacological data emerging from studies on transgenic mice. The possible involvement of ACh in different pathologies has been proposed in recent years and is becoming an important area of study. Although the lack of selective muscarinic receptor ligands has for a long time limited the definition of therapeutic treatment based on muscarinic receptors as targets, some muscarinic ligands such as cevimeline (patents US4855290; US5571918) or xanomeline (patent, US5980933) have been developed and used in pre-clinical or in clinical studies for the treatment of nervous system diseases (Alzheimer' and Sjogren's diseases). The present review focuses on the potential implications of muscarinic receptors in different pathologies, including tumors. Moreover, the future use of muscarinic ligands in therapeutic protocols in cancer therapy will be discussed, considering that some muscarinic antagonists currently used in the treatment of genitourinary disease (e.g. darifenacin, patent, US5096890; US6106864) have also been demonstrated to arrest tumor progression in nude mice. The involvement of muscarinic

  11. RELATIONSHIPS BETWEEN TISSUE LEVELS OF CARBARYL, A PROTOTYPICAL CARBAMATE PESTICIDE, AND CHOLINESTERASE INHIBITION IN LONG EVANS RATS.

    EPA Science Inventory

    As part of an effort to link pharmacokinetics with biochemical and physiological endpoints, the relationships between cholinesterase (ChE) activity and tissue levels of a prototypical N-methyl carbamate pesticide were examined. In a dose-response study, carbaryl (0, 3, 7.5, 15, 3...

  12. Assay techniques for detection of exposure to sulfur mustard, cholinesterase inhibitors, sarin, soman, GF, and cyanide. Technical bulletin

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    NONE

    1996-05-01

    This technical bulletin provides analytical techniques to identify toxic chemical agents in urine or blood samples. It is intended to provide the clinician with laboratory tests to detect exposure to sulfur mustard, cholinesterase inhibitors, sarin, soman, GF, and cyanide.

  13. Plasma cholinesterase inhibition in the clay-colored robin (Turdus grayi) exposed to diazinon in maradol papaya crops in Yucatan, Mexico

    USGS Publications Warehouse

    Cobos, V.M.; Mora, M.A.; Escalona, G.

    2006-01-01

    The use of organophosphorous pesticides in agriculture can result in intoxication of birds foraging in sprayed crops. Effects on birds resulting from pesticide intoxication are varied and include behavioral and reproductive effects, including death. One widely used insecticide in Maradol papaya crops is diazinon which has been associated with various incidents of intoxication and death of wild birds. The objective of this study was to evaluate the impact of diazinon application to papaya crops on plasma cholinesterase activity of the clay-colored robin (Turdus grayi). We captured clay-colored robins foraging in a papaya crop the following day after the field had been sprayed with diazinon at a dose of 1.5 kg/ha during March and May, respectively. We took a blood sample from the brachialis vein of the birds captured and measured plasma enzymatic activity. The plasma samples from birds used as controls were taken during the same time period and were analyzed in a similar way. Enzymatic activity of males was greater than that of females (53,52%) and mean cholinesterase inhibition was 49.43%. Cholinesterase inhibition was greater during May than in March probably due to more continuous exposure and ingestion of the insecticide through food and possible absorption through the skin. This degree of enzymatic inhibition is possibly affecting the behavior of the clay-colored robin and could result in death in severe cases.

  14. An evaluation of neonicotinoids' potential to inhibit human cholinesterases: Protein-ligand docking and interaction profiling studies.

    PubMed

    Teralı, Kerem

    2018-06-16

    Many so-called neuroactive insecticides target invertebrate neurotransmitter systems, including the cholinergic system. With their relatively low toxicity to vertebrates, neonicotinoids represent a new class of neuroactive insecticides that bind to nicotinic receptors for acetylcholine in the insect central nervous system and result in paralysis and eventual death due to receptor overstimulation. On the understanding that, today, cholinesterase inhibitors are used to obtain the symptomatic relief of Alzheimer disease (AD), the aforementioned direct cholinomimetic action of neonicotinoids could, perhaps, confer anti-AD drug-like attributes to these compounds. It is shown here, using protein-ligand docking and interaction profiling, that neonicotinoids penetrate deep into the active-site gorge of both acetylcholinesterase and butyrylcholinesterase and that they form relatively strong noncovalent bonds with multiple critical residues that normally bind/hydrolyze choline esters. With their gorge-spanning shape and dual-binding specificity, neonicotinoids (first-generation compounds in particular) represent promising leads for the development of reversible, mixed-type cholinesterase inhibitors in the fight against AD. Copyright © 2018 Elsevier Inc. All rights reserved.

  15. Synthesis and discovery of novel piperidone-grafted mono- and bis-spirooxindole-hexahydropyrrolizines as potent cholinesterase inhibitors.

    PubMed

    Kia, Yalda; Osman, Hasnah; Kumar, Raju Suresh; Murugaiyah, Vikneswaran; Basiri, Alireza; Perumal, Subbu; Wahab, Habibah A; Bing, Choi Sy

    2013-04-01

    Three-component reaction of a series of 1-acryloyl-3,5-bisbenzylidenepiperidin-4-ones with isatin and L-proline in 1:1:1 and 1:2:2 molar ratios in methanol afforded, respectively the piperidone-grafted novel mono- and bisspiro heterocyclic hybrids comprising functionalized piperidine, pyrrolizine and oxindole ring systems in good yields. The in vitro evaluation of cholinesterase enzymes inhibitory activity of these cycloadducts disclosed that monospiripyrrolizines (8a-k), are more active with IC50 ranging from 3.36 to 20.07 μM than either the dipolarophiles (5a-k) or bisspiropyrrolizines (9a-k). The compounds, 8i and 8e with IC50 values of 3.36 and 3.50 μM, respectively showed the maximum inhibition of acethylcholinesterase (AChE) and butrylylcholinestrase (BuChE). Molecular modeling simulation, disclosed the binding interactions of the most active compounds to the active site residues of their respective enzymes. The docking results were in accordance with the IC50 values obtained from in vitro cholinesterase assay. Copyright © 2013 Elsevier Ltd. All rights reserved.

  16. A new method to characterize the kinetics of cholinesterases inhibited by carbamates.

    PubMed

    Xiao, Qiaoling; Zhou, Huimin; Wei, Hong; Du, Huaqiao; Tan, Wen; Zhan, Yiyi; Pistolozzi, Marco

    2017-09-10

    The inhibition of cholinesterases (ChEs) by carbamates includes a carbamylation (inhibition) step, in which the drug transfers its carbamate moiety to the active site of the enzyme and a decarbamylation (activity recovery) step, in which the carbamyl group is hydrolyzed from the enzyme. The carbamylation and decarbamylation kinetics decide the extent and the duration of the inhibition, thus the full characterization of candidate carbamate inhibitors requires the measurement of the kinetic constants describing both steps. Carbamylation and decarbamylation rate constants are traditionally measured by two separate set of experiments, thus making the full characterization of candidate inhibitors time-consuming. In this communication we show that by the analysis of the area under the inhibition-time curve of cholinesterases inhibited by carbamates it is possible to calculate the decarbamylation rate constant from the same data traditionally used to characterize only the carbamylation kinetics, therefore it is possible to obtain a full characterization of the inhibition with a single set of experiments. The characterization of the inhibition kinetics of human and dog plasma butyrylcholinesterase and of human acetylcholinesterase by bambuterol and bambuterol monocarbamate enantiomers was used to demonstrate the validity of the approach. The results showed that the proposed method provides reliable estimations of carbamylation and decarbamylation rate constants thus representing a simple and useful approach to reduce the time required for the characterization of carbamate inhibitors. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Acquisition and reinstatement of ethanol-induced conditioned place preference in rats: Effects of the cholinesterase inhibitors donepezil and rivastigmine.

    PubMed

    Gawel, Kinga; Labuz, Krzysztof; Gibula-Bruzda, Ewa; Jenda, Malgorzata; Marszalek-Grabska, Marta; Silberring, Jerzy; Kotlinska, Jolanta H

    2016-07-01

    The present study examined the influence of the cholinesterase inhibitors donepezil (a selective inhibitor of acetylcholinesterase) and rivastigmine (also an inhibitor of butyrylcholinesterase) on the acquisition and reinstatement of ethanol-induced conditioned place preference (CPP) in rats. Before the CPP procedure, animals received a single injection of ethanol (0.5 g/kg, 10% w/v, intraperitoneally [i.p.]) for 15 days. The ethanol-induced CPP (biased method) was developed by four injections of ethanol (0.5 g/kg, 10% w/v, i.p.) every second day. Control rats received saline instead of ethanol. Donepezil (0.5, 1 or 3 mg/kg, i.p.) or rivastigmine (0.03, 0.5 or 1 mg/kg, i.p.) were administered before ethanol during conditioning or before the reinstatement of ethanol-induced CPP. The cholinesterase inhibitors were equally effective in increasing (dose dependently) the acquisition of ethanol-induced CPP. Furthermore, priming injections of both inhibitors reinstated (cross-reinstatement) the ethanol-induced CPP with similar efficacy. These effects of both cholinesterase inhibitors were reversed by mecamylamine (3 mg/kg, i.p.), a nicotinic acetylcholine receptor antagonist, but not by scopolamine (0.5 mg/kg, i.p.), a muscarinic acetylcholine receptor antagonist. Thus, our results show that the cholinergic system is involved in the reinforcing properties of ethanol, and nicotinic acetylcholine receptors play an important role in the relapse to ethanol-seeking behaviour. © The Author(s) 2016.

  18. Carbamate derivatives of indolines as cholinesterase inhibitors and antioxidants for the treatment of Alzheimer's disease.

    PubMed

    Yanovsky, Inessa; Finkin-Groner, Efrat; Zaikin, Andrey; Lerman, Lena; Shalom, Hila; Zeeli, Shani; Weill, Tehilla; Ginsburg, Isaac; Nudelman, Abraham; Weinstock, Marta

    2012-12-13

    The cascade of events that occurs in Alzheimer's disease involving oxidative stress and the reduction in cholinergic transmission can be better addressed by multifunctional drugs than cholinesterase inhibitors alone. For this purpose, we prepared a large number of derivatives of indoline-3-propionic acids and esters. They showed scavenging activity against different radicals in solution and significant protection against cytotoxicity in cardiomyocytes and primary cultures of neuronal cells exposed to H2O2 species and serum deprivation at concentrations ranging from 1 nM to 10 μM depending on the compound. For most of the indoline-3-propionic acid derivatives, introduction of N-methyl-N-ethyl or N-methyl-N-(4-methoxyphenyl) carbamate moieties at positions 4, 6, or 7 conferred both acetyl (AChE) and butyryl (BuChE) cholinesterase inhibitory activities at similar concentrations to those that showed antioxidant activity. The most potent AChE inhibitors were 120 (3-(2-aminoethyl) indolin-4-yl ethyl(methyl)carbamate dihydrochloride) and 94 (3-(3-methoxy-3-oxopropyl)-4-(((4-methoxyphenyl)(methyl) carbamoyl)oxy)indolin-1-ium hydrochloride) with IC50s of 0.4 and 1.2 μM, respectively.

  19. Synthesis and in vitro evaluation of novel rhodanine derivatives as potential cholinesterase inhibitors.

    PubMed

    Krátký, Martin; Štěpánková, Šárka; Vorčáková, Katarína; Vinšová, Jarmila

    2016-10-01

    Based on a broad spectrum of biological activities of rhodanines, we synthesized aromatic amides and esters of 2-(4-oxo-2-thioxothiazolidin-3-yl)acetic acid (rhodanine-3-acetic acid) via carbodiimide- or PCl3-mediated coupling. Both esters and amides were investigated for their in vitro inhibitory potency and selectivity against acetylcholinesterase (AChE) from electric eel and butyrylcholinesterase (BChE) from equine serum using Ellman's spectrophotometric method. The derivatives exhibited mostly a moderate activity against both cholinesterases. IC50 values for AChE were in a closer concentration range of 24.05-86.85μM when compared to BChE inhibition (7.92-227.19μM). The esters caused the more efficient inhibition of AChE than amides and parent acid. The esterification and amidation of the rhodanine-3-acetic acid increased inhibition of BChE, even up to 26 times. Derivatives of 4-nitroaniline/phenol showed the activity superior to other substituents (H, Cl, CH3, OCH3, CF3). Rhodanines produced a balanced inhibition of both cholinesterases. Seven derivatives produced the more potent inhibition of AChE than rivastigmine, a clinically used drug; additional three compounds were comparable. Two amides exceeded inhibitory potency of rivastigmine towards BChE. Importantly, this is the first evidence that rhodanine-based compounds are able to inhibit BChE. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Cholinesterase inhibition in meadow voles Microtus pennsylvanicus following field applications of Orthene

    USGS Publications Warehouse

    Jett, David A.

    1986-01-01

    Brain acetylcholinesterase activity in field-caught meadow voles (Microtus pennsylvanicus) was depressed after a field-spray of Orthene (acephate: acetylphosphoramidothioic acid O,S-dimethyl ester) by as much as 32% in 1982 and 38% in 1983. Short-term recovery was demonstrated and occurred in a time-dependent fashion in 1982. Plasma cholinesterase levels were move variable but also were depressed. Residues were detected in vegetation samples and in the gastrointestinal tracts of exposed voles. Residues in vegetation were diluted or absent 7 to 8 d following the treatment.

  1. International Meeting on Cholinesterases (5th) Held in Madras, India on 24-28 September, 1994.

    DTIC Science & Technology

    1994-09-01

    AChE activity . 67 Session F: Structure-Function Relationship of Anticholinesterase Agents: Pesticides and Therapeutic Agents; Noncholinergic Function... plants . The activity of two cholinesterases: acetylcholinesterase [E.C. 3.1.1.7] and butyrylcholinesterase [E.C. 3.1.1.81 was found in homogenates from...was tested in vitro. POSTER NO. 27: ACETYLCHOLINESTERASE ACTIVITY IN PLANTS . S. Madhavan and Gautam Sarath. Department of Biochemistry, University of

  2. Synthesis and in vitro evaluation of new derivatives of 2-substituted-6-fluorobenzo[d]thiazoles as cholinesterase inhibitors.

    PubMed

    Imramovský, Aleš; Pejchal, Vladimír; Štěpánková, Šárka; Vorčáková, Katarína; Jampílek, Josef; Vančo, Ján; Šimůnek, Petr; Královec, Karel; Brůčková, Lenka; Mandíková, Jana; Trejtnar, František

    2013-04-01

    A series of novel cholinesterase inhibitors based on 2-substituted 6-fluorobenzo[d]thiazole were synthesised and characterised by IR, (1)H, (13)C and (19)F NMR spectroscopy and HRMS. Purity was checked by elemental analyses. The novel carbamates were tested for their ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The toxicity of the most active compounds was investigated using a standard in vitro test with HepG2 cells, and the ratio between biological activity and toxicity was determined. In addition, the toxicity of the most active compounds was evaluated against MCF7 cells using the xCELLigence system. Structure-activity relationships reflecting the dependence of cholinesterase inhibitors on the lipophilicity of the compounds as well as on the Taft polar and steric substituent constants are discussed. The specific orientation of the inhibitors in the binding site of acetylcholinesterase was determined using molecular docking of the most active compound. Copyright © 2013 Elsevier Ltd. All rights reserved.

  3. Specific radioisotopic assay for cholinesterase

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Talbot, B.G.; Anderson, D.R.; Harris, L.W.

    1992-02-01

    The authors have developed a radiometric method (1) for measuring cholinesterase (ChE) activity that uses 0.4 N perchloric acid (PCA), instead of p-dioxane (method 2), to denature the ChE and stop hydrolysis of acetyl-1-{sup 14}C-choline (ACh). The unreacted ACh is removed by IRP-69 cationic exchange resin suspended in water, instead of dioxane. The supernatant containing the hydrolysis product, {sup 14}C-acetic acid, is mixed with nonhazardous scintillation cocktail and counted. The incubation mixture of 1 is similar to 2 and contains 0.1 ml of buffer-salt solution 0.1 ml of guinea pig whole blood (WB)-water suspension and 0.1 ml of 3 mMmore » ACh solution. Procedures 1 and 2 were compared to a titragraphic assay for ChE activity; specific activity values of WB (mmol ACh hydrolyzed/ml/hr) were found to be 137.6, 72.4 and 135.0, respectively. When {sup 14}C-acetic acid was processed through procedures 1 and 2, significantly less {sup 14}C was found in the supernatant from 2, whereas all of the expected {sup 14}C was found in the supernatant from 1, suggesting that IRP-69 resin in dioxane will remove significant amounts of {sup 14}C-acetic acid.« less

  4. [COMPARATIVE SENSITIVITY OF CHOLINESTERASES IN VERTEBRATES AND INVERTEBRATES TO HIGHLY SPECIFIC ORGANOPHOSPHORUS INHIBITORS DIISOPROPYL FLUOROPHOSPHATE (DFP) AND (2-ETHOXYMETHYL PHOSPHORYL THIOETHYL) ETHYL (METHYL) SULPHONIUM SULPHOMETHYLAT (GD-42)].

    PubMed

    Basova, N E; Kormilitsyn, B N; Perchenok, A Yu; Rozengart, E V; Saakov, V S; Suvorov, A A

    2015-01-01

    The review presents data on comparative reactivity of 68 cholinesterase preparation from various organs and tissues in a number of vertebrates and invertebrates based on sensitivity to two highly specific and most studied organophosphorus inhibitors--diisopropyl fluorophosphates (DFP) and (2-ethoxymethyl phosphoryl thioethyl) ethyl (methyl) sulphonium sulphomethylat (GD-42). Analysis of these data suggests a great diversity in enzymologic characteristics of cholinesterase preparation in representatives of vertebrates and invertebrates, this variety observed even for closely related enzymes in animals of almost the same level of development.

  5. The NADPH oxidase inhibitor diphenyleneiodonium is also a potent inhibitor of cholinesterases and the internal Ca2+ pump

    PubMed Central

    Tazzeo, T; Worek, F; Janssen, LJ

    2009-01-01

    Background and purpose: Diphenyleneiodonium (DPI) is often used as an NADPH oxidase inhibitor, but is increasingly being found to have unrelated side effects. We investigated its effects on smooth muscle contractions and the related mechanisms. Experimental approach: We studied isometric contractions in smooth muscle strips from bovine trachea. Cholinesterase activity was measured using a spectrophotometric assay; internal Ca2+ pump activity was assessed by Ca2+ uptake into smooth muscle microsomes. Key results: Contractions to acetylcholine were markedly enhanced by DPI (10−4 M), whereas those to carbachol (CCh) were not, suggesting a possible inhibition of cholinesterase. DPI markedly suppressed contractions evoked by CCh, KCl and 5-HT, and also unmasked phasic activity in otherwise sustained responses. Direct biochemical assays confirmed that DPI was a potent inhibitor of acetylcholinesterase and butyrylcholinesterase (IC50∼8 × 10−6 M and 6 × 10−7 M, respectively), following a readily reversible, mixed non-competitive type of inhibition. The inhibitory effects of DPI on CCh contractions were not mimicked by another NADPH oxidase inhibitor (apocynin), nor the Src inhibitors PP1 or PP2, ruling out an action through the NADPH oxidase signalling pathway. Several features of the DPI-mediated suppression of agonist-evoked responses (i.e. suppression of peak magnitudes and unmasking of phasic activity) are similar to those of cyclopiazonic acid, an inhibitor of the internal Ca2+ pump. Direct measurement of microsomal Ca2+ uptake revealed that DPI modestly inhibits the internal Ca2+ pump. Conclusions and implications: DPI inhibits cholinesterase activity and the internal Ca2+ pump in tracheal smooth muscle. PMID:19788497

  6. Cholinesterase Inhibitors Improve Both Memory and Complex Learning in Aged Beagle Dogs

    PubMed Central

    Araujo, Joseph A.; Greig, Nigel H.; Ingram, Donald K.; Sandin, Johan; de Rivera, Christina; Milgram, Norton W.

    2016-01-01

    Similar to patients with Alzheimer’s disease (AD), dogs exhibit age-dependent cognitive decline, amyloid-β (Aβ) pathology, and evidence of cholinergic hypofunction. The present study sought to further investigate the role of cholinergic hypofunction in the canine model by examining the effect of the cholinesterase inhibitors phenserine and donepezil on performance of two tasks, a delayed non-matching-to-position task (DNMP) designed to assess working memory, and an oddity discrimination learning task designed to assess complex learning, in aged dogs. Phenserine (0.5 mg/kg; PO) significantly improved performance on the DNMP at the longest delay compared to wash-out and partially attenuated scopolamine-induced deficits (15 μg/kg; SC). Phenserine also improved learning on a difficult version of an oddity discrimination task compared to placebo, but had no effect on an easier version. We also examined the effects of three doses of donepezil (0.75, 1.5, and 6 mg/kg; PO) on performance of the DNMP. Similar to the results with phenserine, 1.5 mg/kg of donepezil improved performance at the longest delay compared to baseline and wash-out, indicative of memory enhancement. These results further extend the findings of cholinergic hypofunction in aged dogs and provide pharmacological validation of the canine model with a cholinesterase inhibitor approved for use in AD. Collectively, these studies support utilizing the aged dog in future screening of therapeutics for AD, as well as for investigating the links among cholinergic function, Aβ pathology, and cognitive decline. PMID:21593569

  7. CHOLINESTERASE INHIBITION AND HYPOTHERMIA FOLLOWING EXPOSURE TO BINARY MIXTURES OF ANTICHOLINESTERASE AGENTS: LACK OF EVIDENCE FOR CAUSE-AND-EFFECT

    EPA Science Inventory

    Dose-additivity has been the default assumption in risk assessments of pesticides with a common mechanism of action but it has been suspected that there could be non-additive effects. Inhibition of plasma cholinesterase (ChE) activity and hypothermia were used as benchmarks of e...

  8. New advances in pharmacological approaches to the cholinergic system: an overview on muscarinic receptor ligands and cholinesterase inhibitors

    PubMed Central

    Greig, Nigel H.; Reale, Marcella; Tata, Ada Maria

    2016-01-01

    The cholinergic system is expressed in neuronal and in non-neuronal tissues. Acetylcholine (ACh), synthesized in and out of the nervous system can locally contribute to modulation of various cell functions (e.g. survival, proliferation). Considering that the cholinergic system and its functions are impaired in a number of disorders, the identification of new pharmacological approaches to regulate cholinergic system components appears of great relevance. The present review focuses on recent pharmacological drugs able to modulate the activity of cholinergic receptors and thereby, cholinergic function, with an emphasis on the muscarinic receptor subtype, and additionally covers the cholinesterases, the main enzymes involved in ACh hydrolysis. The presence and function of muscarinic receptor subtypes both in neuronal and non-neuronal cells has been demonstrated using extensive pharmacological data emerging from studies on transgenic mice. The possible involvement of ACh in different pathologies has been proposed in recent years and is becoming an important area of study. Although the lack of selective muscarinic receptor ligands has for a long time limited the definition of therapeutic treatment based on muscarinic receptors as targets, some muscarinic ligands such as cevimeline (patents US4855290; US5571918) or xanomeline (patent, US5980933) have been developed and used in pre-clinical or in clinical studies for the treatment of nervous system diseases (Alzheimer’ and Sjogren’s diseases). The present review focuses on the potential implications of muscarinic receptors in different pathologies, including tumors. Moreover, the future use of muscarinic ligands in therapeutic protocols in cancer therapy will be discussed, considering that some muscarinic antagonists currently used in the treatment of genitourinary disease (e.g. darifenacin, patent, US5096890; US6106864) have also been demonstrated to arrest tumor progression in nude mice. The involvement of muscarinic

  9. Cholinesterases as markers of the inflammatory process associated oxidative stress in cattle infected by Babesia bigemina.

    PubMed

    Doyle, Rovaina L; Da Silva, Aleksandro S; Oliveira, Camila B; França, Raqueli T; Carvalho, Fabiano B; Abdalla, Fátima H; Costa, Pauline; Klafke, Guilherme M; Martins, João R; Tonin, Alexandre A; Castro, Verônica S P; Santos, Franklin G B; Lopes, Sonia T A; Andrade, Cinthia M

    2016-06-01

    The objective of this study was to assess the influence of an asymptomatic experimental infection by Babesia bigemina on cholinesterase's as markers of the inflammatory process and biomarkers of oxidative imbalance. For this purpose, eight naive animals were used, as follows: four as controls or uninfected; and four infected with an attenuated strain of B. bigemina. Blood samples were collected on days 0, 7 and 11 post-inoculation (PI). Parasitemia was determined by blood smear evaluation, showing that the infection by B. bigemina resulted in mean 0.725 and 0.025% on day 7 and 11 PI, respectively, as well as mild anemia. The activities of acetylcholinesterase, butyrylcholinesterase and catalase were lower, while levels of thiobarbituric acid reactive substances and superoxide dismutase activity were higher in infected animals, when compared with the control group. This attenuated strain of B. bigemina induced an oxidative stress condition, as well as it reduces the cholinesterasés activity in infected and asymptomatic cattle. Therefore, this decrease of cholinesterase in infection by B. bigemina purpose is to inhibit inflammation, for thereby increasing acetylcholine levels, potent anti-inflammatory molecules. Copyright © 2016. Published by Elsevier Ltd.

  10. [Isomeric derivatives of lupinine and epilupinine--organophosphorus inhibitors of cholinesterases].

    PubMed

    Basova, N E; Kormilitsyn, B N; Perchenok, A Iu; Rosengart, E V; Saakov, V S; Suvorov, A A

    2012-01-01

    The isomeric-structure analysis data of anticholinesterase action of organophosphorous inhibitors with similar structure help in the search of specific effectors and detection of differences in reactivity of various animals' enzymes. This study compared the data of efficacy in respect of 4 mammal and 5 arthropoda cholinesterase preparations for 26 quinolizidine inhibitors, which molecules contain both the isomeric unbranched and branched alkoxyl radicals in the phosphoryl group, and the epimeric lupinine and epilupinine derivatives in the leaving group. The changes in the alkoxyl radical structure of inhibitor molecules act on their efficacy only with respect to the mammal enzymes ("group" inhibitor specificity). The differences between lupinine and epilupinine derivatives were revealed. Highly specific inhibitors of different enzymes were detected among the tested compounds.

  11. Modulation of fusiform cortex activity by cholinesterase inhibition predicts effects on subsequent memory.

    PubMed

    Bentley, P; Driver, J; Dolan, R J

    2009-09-01

    Cholinergic influences on memory are likely to be expressed at several processing stages, including via well-recognized effects of acetylcholine on stimulus processing during encoding. Since previous studies have shown that cholinesterase inhibition enhances visual extrastriate cortex activity during stimulus encoding, especially under attention-demanding tasks, we tested whether this effect correlates with improved subsequent memory. In a within-subject physostigmine versus placebo design, we measured brain activity with functional magnetic resonance imaging while healthy and mild Alzheimer's disease subjects performed superficial and deep encoding tasks on face (and building) visual stimuli. We explored regions in which physostigmine modulation of face-selective neural responses correlated with physostigmine effects on subsequent recognition performance. In healthy subjects physostigmine led to enhanced later recognition for deep- versus superficially-encoded faces, which correlated across subjects with a physostigmine-induced enhancement of face-selective responses in right fusiform cortex during deep- versus superficial-encoding tasks. In contrast, the Alzheimer's disease group showed neither a depth of processing effect nor restoration of this with physostigmine. Instead, patients showed a task-independent improvement in confident memory with physostigmine, an effect that correlated with enhancements in face-selective (but task-independent) responses in bilateral fusiform cortices. Our results indicate that one mechanism by which cholinesterase inhibitors can improve memory is by enhancing extrastriate cortex stimulus selectivity at encoding, in a manner that for healthy people but not in Alzheimer's disease is dependent upon depth of processing.

  12. Cholinesterase targeting by polyphenols: A therapeutic approach for the treatment of Alzheimer's disease.

    PubMed

    Jabir, Nasimudeen R; Khan, Fayaz Rahman; Tabrez, Shams

    2018-05-16

    Alzheimer's disease (AD) is a progressive irreversible neurodegenerative disorder characterized by excessive deposition of β-amyloid (Aβ) oligomers, and neurofibrillary tangles (NFTs), comprising of hyperphosphorylated tau proteins. The cholinergic system has been suggested as the earliest and most affected molecular mechanism that describes AD pathophysiology. Moreover, cholinesterase inhibitors (ChEIs) are the potential class of drugs that can amplify cholinergic activity to improve cognition and global performance and reduce psychiatric and behavioral disturbances. Approximately, 60%-80% of all cases of dementia in the world are patients with AD. In view of the continuous rise of this disease especially in the aged population, there is a dire need to come up with a novel compound and/or mixture that could work against this devastating disease. In this regard, the best is to rely on natural compounds rather than synthetic ones, because natural compounds are easily available, cost-effective, and comparatively less toxic. To serve this purpose, lately, scientific community has started exploring the possibility of using different polyphenols either solitary or in combination that can serve as therapeutics against AD. In the current article, we have summarized the role of various polyphenols, namely quercetin, resveratrol, curcumin, gallocatechins, cinnamic acid, caffeine, and caffeic acid as an inhibitor of cholinesterase for the treatment of AD. We have also tried to uncover the mechanistic insight on the action of these polyphenols against AD pathogenicity. © 2018 John Wiley & Sons Ltd.

  13. INHIBITION OF BRAIN CHOLINESTERASE AND THE PHOTIC AFTER DISCHARGE OF FLASH EVOKED POTENTIALS PRODUCED BY CARBARYL IN LONG EVANS RATS.

    EPA Science Inventory

    Carbaryl is a widely used N-methyl carbamate pesticide that acts by inhibiting cholinesterases (ChE), which may lead to cholinergic toxicity. Flash evoked potentials (FEPs) are a neurophysiological response often used to detect central nervous system (CNS) changes following expos...

  14. Variation of Cholinesterase-Based Biosensor Sensitivity to Inhibition by Organophosphate Due To Ionizing Radiation

    PubMed Central

    Pohanka, Miroslav; Koch, Miroslav

    2009-01-01

    A cholinesterase based biosensor was constructed in order to assess the effects of ionizing radiation on exposed AChE. Although the primary objective of the experiment was to investigate the effect of ionizing radiation on the activity of the biosensor, no changes in cholinesterase activity were observed. Current provided by oxidation of thiocholine previously created from acetylthiocholine by enzyme catalyzed reaction was in a range 395–455 nA. No significant influence of radiation on AChE activity was found, despite the current variation. However, a surprising phenomenon was observed when a model organophosphate paraoxon was assayed. Irradiated biosensors seem to be more susceptible to the inhibitory effects of paraoxon. Control biosensors provided a 94 ± 5 nA current after exposure to 1 ppm paraoxon. The biosensors irradiated by a 5 kGy radiation dose and exposed to paraoxon provided a current of 49 ± 6 nA. Irradiation by doses ranging from 5 mGy to 100 kGy were investigated and the mentioned effect was confirmed at doses above 50 Gy. After the first promising experiments, biosensors irradiated by 5 kGy were used for calibration on paraoxon and compared with the control biosensors. Limits of detection 2.5 and 3.8 ppb were achieved for irradiated and non-irradiated biosensors respectively. The overall impact of this effect is discussed. PMID:22346715

  15. In-silico identification of the binding mode of synthesized adamantyl derivatives inside cholinesterase enzymes

    PubMed Central

    Al-Aboudi, Amal; Al-Qawasmeh, Raed A; Shahwan, Alaa; Mahmood, Uzma; Khalid, Asaad; Ul-Haq, Zaheer

    2015-01-01

    Aim: To investigate the binding mode of synthesized adamantly derivatives inside of cholinesterase enzymes using molecular docking simulations. Methods: A series of hybrid compounds containing adamantane and hydrazide moieties was designed and synthesized. Their inhibitory activities against acetylcholinesterase (AChE) and (butyrylcholinesterase) BChE were assessed in vitro. The binding mode of the compounds inside cholinesterase enzymes was investigated using Surflex-Dock package of Sybyl7.3 software. Results: A total of 26 adamantyl derivatives were synthesized. Among them, adamantane-1-carboxylic acid hydrazide had an almost equal inhibitory activity towards both enzymes, whereas 10 other compounds exhibited moderate inhibitory activity against BChE. The molecular docking studies demonstrated that hydrophobic interactions between the compounds and their surrounding residues in the active site played predominant roles, while hydrophilic interactions were also found. When the compounds were docked inside each enzyme, they exhibited stronger interactions with BChE over AChE, possibly due to the larger active site of BChE. The binding affinities of the compounds for BChE and AChE estimated were in agreement with the experimental data. Conclusion: The new adamantly derivatives selectively inhibit BChE with respect to AChE, thus making them good candidates for testing the hypothesis that BChE inhibitors would be more efficient and better tolerated than AChE inhibitors in the treatment of Alzheimer's disease. PMID:25937631

  16. Brain region-specific effects of immobilization stress on cholinesterases in mice.

    PubMed

    Valuskova, Paulina; Farar, Vladimir; Janisova, Katerina; Ondicova, Katarina; Mravec, Boris; Kvetnansky, Richard; Myslivecek, Jaromir

    2017-01-01

    Brain acetylcholinesterase (AChE) variant AChE R expression increases with acute stress, and this persists for an extended period, although the timing, strain and laterality differences, have not been explored previously. Acute stress transiently increases acetylcholine release, which in turn may increase activity of cholinesterases. Also the AChE gene contains a glucocorticoid response element (GRE), and stress-inducible AChE transcription and activity changes are linked to increased glucocorticoid levels. Corticotropin-releasing hormone knockout (CRH-KO) mice have basal glucocorticoid levels similar to wild type (WT) mice, but much lower levels during stress. Hence we hypothesized that CRH is important for the cholinesterase stress responses, including butyrylcholinesterase (BChE). We used immobilization stress, acute (30 or 120 min) and repeated (120 min daily × 7) in 48 male mice (24 WT and 24 CRH-KO) and determined AChE R , AChE and BChE mRNA expression and AChE and BChE activities in left and right brain areas (as cholinergic signaling shows laterality). Immobilization decreased BChE mRNA expression (right amygdala, to 0.5, 0.3 and 0.4, × control respectively) and AChE R mRNA expression (to 0.5, 0.4 and 0.4, × control respectively). AChE mRNA expression increased (1.3, 1.4 and 1.8-fold, respectively) in the left striatum (Str). The AChE activity increased in left Str (after 30 min, 1.2-fold), decreased in right parietal cortex with repeated stress (to 0.5 × control). BChE activity decreased after 30 min in the right CA3 region (to 0.4 × control) but increased (3.8-fold) after 120 min in the left CA3 region. The pattern of changes in CRH-KO differed from that in WT mice.

  17. TIME COURSE OF CHOLINESTERASE INHIBITION IN ADULT RATS TREATED ACUTELY WITH CARBARYL CARBOFURAN, FORMETANATE, METHOMYL, METHIOCARB, OXAMYL ON PROPOXUR.

    EPA Science Inventory

    To compare the toxicity of seven N-methyl carbamates, time course profiles for brain and red blood cell (RBC) cholinesterase (ChE) inhibition were established for each. Adult, male, Long Evans rats (n=4-5 dose group) were dosed orally with either carbaryl (30 mg/kg in corn oil); ...

  18. [The influence of sodium bicarbonate combined with ulinastatin on cholinesterase activity for patients with acute phoxim pesticide poisoning].

    PubMed

    Zhao, Bo; Yang, Lanju; Xiao, Lei; Sun, Baoquan; Zou, Xianbao; Gao, Dongmei; Jian, Xiandong

    2016-01-01

    To observe the effect of sodium bicarbonate combined with ulinastatin on cholinesterase activity for patients with acute phoxim pesticide poisoning. A total of 67 eligible patients with acute phoxim pesticide poisoning, Who were admitted to the emeryency department of hospital from March 2011 to February 2014, Acording to different treatments au patients were randomly divided into the conventional treatment group (n=34) and the sodium bicarbonate+ulinastatin group (n=35) . The conventional treatment group were given thorough gastric lavage with water, the sodium bicarbonate + ulinastatin group were given gastric lavage with 2% sodium bicarbonate solution. Both groups were given such treatments as catharsis, administration of oxygen, fluid infusion, diuresis, and antidotes such as atropine and pralidoxime methylchloride. On the basis of comprehensive treatment, people in the sodium bicarbonate+ulinastatin group were given 5% sodium bicarbonate injection and ulinastatin. The clinical effect of the two groups were compared. The serum cholinesterase activity of the sodium bicarbonate+ulinastatin group was significantly higher than the conventional treatment group from the 5th day, and the difference was statistically significant (P<0.05) . The total atropine dosage, total pralidoxime methylchloride dosage and hospitalization days were better than the conventional treatment group, and the differences were statistically significant (P<0.05) . The difference in the time of atropinization between the two groups was not statistically significant (P>0.05) . The results of arterial blood pH, HCO3- of the sodium bicarbonate + ulinastatin group were higher than the conventional treatment group, and the difference of HCO3- at the 10th day was statistically significant (P<0.05) . Sodium bicarbonate combined with ulinastatin can improve the therapeutic effect and reduce complications in the treatment of acute phoxim pesticide poisoning, and have beneficial effects on the recovery

  19. Different sensitivities of rat skeletal muscles and brain to novel anti-cholinesterase agents, alkylammonium derivatives of 6-methyluracil (ADEMS)

    PubMed Central

    Petrov, Konstantin A; Yagodina, Lilia O; Valeeva, Guzel R; Lannik, Natalya I; Nikitashina, Alexandra D; Rizvanov, Albert A; Zobov, Vladimir V; Bukharaeva, Ellya A; Reznik, Vladimir S; Nikolsky, Eugeny E; Vyskočil, František

    2011-01-01

    BACKGROUND AND PURPOSE The rat respiratory muscle diaphragm has markedly lower sensitivity than the locomotor muscle extensor digitorum longus (EDL) to the new acetylcholinesterase (AChE) inhibitors, alkylammonium derivatives of 6-methyluracil (ADEMS). This study evaluated several possible reasons for differing sensitivity between the diaphragm and limb muscles and between the muscles and the brain. EXPERIMENTAL APPROACH Increased amplitude and prolonged decay time of miniature endplate currents were used to assess anti-cholinesterase activity in muscles. In hippocampal slices, induction of synchronous network activity was used to follow cholinesterase inhibition. The inhibitor sensitivities of purified AChE from the EDL and brain were also estimated. KEY RESULTS The intermuscular difference in sensitivity to ADEMS is partly explained caused by a higher level of mRNA and activity of 1,3-bis[5(diethyl-o-nitrobenzylammonium)pentyl]-6-methyluracildibromide (C-547)-resistant BuChE in the diaphragm. Moreover, diaphragm AChE was more than 20 times less sensitive to C-547 than that from the EDL. Sensitivity of the EDL to C-547 dramatically decreased after treadmill exercises that increased the amount of PRiMA AChE(G4), but not ColQ AChE(A12) molecular forms. The A12 form present in muscles appeared more sensitive to C-547. The main form of AChE in brain, PRiMA AChE(G4), was apparently less sensitive because brain cholinesterase activity was almost three orders of magnitude more resistant to C-547 than that of the EDL. CONCLUSIONS AND IMPLICATIONS Our findings suggest that ADEMS compounds could be used for the selective inhibition of AChEs and as potential therapeutic tools. PMID:21232040

  20. Possible long-term health effects of short-term exposure to chemical agents. Volume 2. Cholinesterase reactivators, psychochemicals, and irritants and vesicants. Final report

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Not Available

    1984-01-01

    The present report evaluates toxicologic and epidemiologic data relevant to the testing of approximately 750 subjects exposed to cholinesterase reactivators, about 260 exposed to psychochemicals, and 1,500 exposed to irritants or vesicants. A remaining group of subjects used largely in tests involving placebo or innocuous chemicals or conditions is available for comparison and will be discussed later. The report is the work of three panels of scientists--the Panel on Cholinesterase Reactivator Chemicals, the Panel on Psychochemicals, and the Panel on Irritants and Vesicants. The chairman of each panel was selected from the Committee on Toxicology, and the members were selectedmore » on the basis of their knowledge of the compounds in question or because they represented required disciplines.« less

  1. Comparative Risk of Pneumonia Among New Users of Cholinesterase Inhibitors for Dementia

    PubMed Central

    Lai, Edward Chia-Cheng; Wong, Monera B.; Iwata, Isao; Zhang, Yinghong; Hsieh, Cheng-Yang; Yang, Yea-Huei Kao; Setoguchi, Soko

    2015-01-01

    OBJECTIVES To compare the risk of pneumonia among older patients receiving donepezil, galantamine, or rivastigmine for dementia. DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study of a nationally representative 5% sample of Medicare beneficiaries 65 years or older who newly initiated cholinesterase inhibitor therapy between 2006 and 2009. MEASUREMENTS Pneumonia, defined as the presence of a diagnosis code for pneumonia as the primary diagnosis on an inpatient claim or on an emergency department claim followed by dispensing of appropriate antibiotics. We used Cox proportional hazards models to estimate the risk of pneumonia. We conducted secondary analyses and sensitivity analyses using alternative pneumonia definitions and adjustments by high-dimensional propensity scores to test the robustness of the results. RESULTS Among 35,570 new users of cholinesterase inhibitors (30,174 users of donepezil, 1176 users of galantamine, and 4220 users of rivastigmine), mean age was 82 years, 75% were women, and 82% were white. The cumulative incidence of pneumonia was 51.9 per 1000 person-years. Risk was significantly lower by 24% among rivastigmine users compared with donepezil users (hazard ratio [HR], 0.75; 95% CI, 0.60–0.93). Risk among galantamine users (HR, 0.87; 95% CI, 0.62–1.23) was not significantly different from risk among donepezil users. Results of secondary and sensitivity analyses were similar to the primary results. CONCLUSION The risk of pneumonia was lower among patients receiving rivastigmine compared with patients receiving donepezil. Additional studies are needed to confirm the findings of pneumonia risk between the oral and transdermal forms of rivastigmine and among users of galantamine. PMID:25912671

  2. Sex and storage affect cholinesterase activity in blood plasma of Japanese quail

    USGS Publications Warehouse

    Hill, E.F.

    1989-01-01

    Freezing at -25?C had confounding effects on cholinesterase (ChE) activity in blood plasma from breeding female quail, but did not affect ChE activity in plasma from males. Plasma ChE activity of control females increased consistently during 28 days of storage while both carbamate- and cidrotophos-inhibited ChE decreased. Refrigeration of plasma at 4?C for 2 days had little effect of ChE activity. Plasma ChE activity was averaged about 34% higher in breeding males than in females. Extreme caution should be exercised in use of blood plasma for evaluation of anti ChE exposure in free-living birds.

  3. Activity of cholinesterases and adenosine deaminase in blood and serum of rats experimentally infected with Trypanosoma cruzi

    PubMed Central

    DA SILVA, A S; PIMENTEL, V C; FIORENZA, A M; FRANÇA, R T; TONIN, A A; JAQUES, J A; LEAL, C A M; DA SILVA, C B; MORSCH, V; SCHETINGER, M R C; LOPES, S T A; MONTEIRO, S G

    2011-01-01

    This study aimed to evaluate the activity of cholinesterases and adenosine deaminase (ADA) in blood and serum of rats infected with Trypanosoma cruzi. Twelve adult rats were used in the experiment divided into two uniform groups. Rodents from group A (control group) were non-infected and animals from group B served as infected, receiving intraperitoneally 3.3×107 trypomastigotes/each. Blood collection was performed at days 60 and 120 post-infection (PI) in order to evaluate the hemogram, blood activity of acetylcholinesterase, and serum butyrylcholinesterase and ADA activities. Hematological parameters did not differ between groups. A significant increase (P<0.05) of acetylcholinesterase activity was observed in blood while butyrylcholinesterase had a significant reduction (P<0.01) in serum of infected rats at days 60 and 120 PI. ADA activity in serum showed an inhibition in infected animals when compared to non-infected at day 120 PI. Based on these results, it is possible to conclude that the activity of cholinesterases and ADA were changed in animals infected with T. cruzi. The possible causes of these alterations will be discussed in this paper. PMID:21929880

  4. Synthesis, pharmacology and molecular docking on multifunctional tacrine-ferulic acid hybrids as cholinesterase inhibitors against Alzheimer's disease.

    PubMed

    Zhu, Jie; Yang, Hongyu; Chen, Yao; Lin, Hongzhi; Li, Qi; Mo, Jun; Bian, Yaoyao; Pei, Yuqiong; Sun, Haopeng

    2018-12-01

    The cholinergic hypothesis has long been a "polar star" in drug discovery for Alzheimer's disease (AD), resulting in many small molecules and biological drug candidates. Most of the drugs marketed for AD are cholinergic. Herein, we report our efforts in the discovery of cholinesterases inhibitors (ChEIs) as multi-target-directed ligands. A series of tacrine-ferulic acid hybrids have been designed and synthesised. All these compounds showed potent acetyl-(AChE) and butyryl cholinesterase(BuChE) inhibition. Among them, the optimal compound 10g, was the most potent inhibitor against AChE (electrophorus electricus (eeAChE) half maximal inhibitory concentration (IC 50 ) = 37.02 nM), it was also a strong inhibitor against BuChE (equine serum (eqBuChE) IC 50  = 101.40 nM). Besides, it inhibited amyloid β-protein self-aggregation by 65.49% at 25 μM. In subsequent in vivo scopolamine-induced AD models, compound 10g obviously ameliorated the cognition impairment and showed preliminary safety in hepatotoxicity evaluation. These data suggest compound 10g as a promising multifunctional agent in the drug discovery process against AD.

  5. Prenylated xanthones from mangosteen as promising cholinesterase inhibitors and their molecular docking studies.

    PubMed

    Khaw, K Y; Choi, S B; Tan, S C; Wahab, H A; Chan, K L; Murugaiyah, V

    2014-09-25

    Garcinia mangostana is a well-known tropical plant found mostly in South East Asia. The present study investigated acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities of G. mangostana extract and its chemical constituents using Ellman's colorimetric method. Cholinesterase inhibitory-guided approach led to identification of six bioactive prenylated xanthones showing moderate to potent cholinesterases inhibition with IC50 values of lower than 20.5 μM. The most potent inhibitor of AChE was garcinone C while γ-mangostin was the most potent inhibitor of BChE with IC50 values of 1.24 and 1.78 μM, respectively. Among the xanthones, mangostanol, 3-isomangostin, garcinone C and α-mangostin are AChE selective inhibitors, 8-deoxygartanin is a BChE selective inhibitor while γ-mangostin is a dual inhibitor. Preliminary structure-activity relationship suggests the importance of the C-8 prenyl and C-7 hydroxy groups for good AChE and BChE inhibitory activities. The enzyme kinetic studies indicate that both α-mangostin and garcinone C are mixed-mode inhibitors, while γ-mangostin is a non-competitive inhibitor of AChE. In contrast, both γ-mangostin and garcinone C are uncompetitive inhibitors, while α-mangostin is a mixed-mode inhibitor of BChE. Molecular docking studies revealed that α-mangostin, γ-mangostin and garcinone C interacts differently with the five important regions of AChE and BChE. The nature of protein-ligand interactions is mainly hydrophobic and hydrogen bonding. These bioactive prenylated xanthones are worthy for further investigations. Copyright © 2014 Elsevier GmbH. All rights reserved.

  6. State-wide hospital clinical laboratory plan for measuring cholinesterase activity for individuals suspected of exposure to nerve agent chemical weapons.

    PubMed

    Wu, Alan H B; Smith, Andrew; McComb, Robert; Bowers, George N; Makowski, Gregory S; McKay, Charles A; Vena, Jason; McDonagh, John; Hopfer, Sidney; Sena, Salvatore F; Malkus, Herbert; Forte, Elaine; Kelly, Katherine

    2008-02-01

    Hospital laboratories currently lack the capacity to provide emergency determination of cholinesterase activity. We have developed a hospital-based 3-tiered system to test plasma for butyrylcholinesterase (BChE) activity and whole blood for red cell acetylcholinesterase (AChE) activity using available technology and personnel. Interagency communications, toxidrome definition, and patient triage will be coordinated by the Connecticut Department of Public Health and the Poison Control Center. Initial BChE data documents good precision between institutions (coefficient of variation < 8%). Laboratory testing of plasma or blood for cholinesterase activity is important in the management of nerve agent exposure and in ruling out disease in those with non-specific symptoms in the setting of a terrorist attack or accidental exposure. Rapid availability of strong hospital-based analytic support in a smoothly functioning network of clinical, public health, and laboratory services will facilitate overall regional response to chemical terrorism or large scale HazMat events.

  7. Ramalina capitata (Ach.) Nyl. acetone extract: HPLC analysis, genotoxicity, cholinesterase, antioxidant and antibacterial activity.

    PubMed

    Zrnzevic, Ivana; Stankovic, Miroslava; Stankov Jovanovic, Vesna; Mitic, Violeta; Dordevic, Aleksandra; Zlatanovic, Ivana; Stojanovic, Gordana

    2017-01-01

    In the present investigation, effects of Ramalina capitata acetone extract on micronucleus distribution on human lymphocytes, on cholinesterase activity and antioxidant activity (by the CUPRAC method) were examined, for the first time as well as its HPLC profile. Additionally, total phenolic compounds (TPC), antioxidant properties (estimated via DPPH, ABTS and TRP assays) and antibacterial activity were determined. The predominant phenolic compounds in this extract were evernic, everninic and obtusatic acids. Acetone extract of R. capitata at concentration of 2 μg mL -1 decreased a frequency of micronuclei (MN) for 14.8 %. The extract reduces the concentration of DPPH and ABTS radicals for 21.2 and 36.1 % (respectively). Values for total reducing power (TRP) and cupric reducing capacity (CUPRAC) were 0.4624 ± 0.1064 μg ascorbic acid equivalents (AAE) per mg of dry extract, and 6.1176 ± 0.2964 μg Trolox equivalents (TE) per mg of dry extract, respectively. The total phenol content was 670.6376 ± 66.554 μg galic acid equivalents (GAE) per mg of dry extract. Tested extract at concentration of 2 mg mL -1 exhibited inhibition effect (5.2 %) on pooled human serum cholinesterase. The antimicrobial assay showed that acetone extract had inhibition effect towards Gram-positive strains. The results of manifested antioxidant activity, reducing the number of micronuclei in human lymphocytes, and antibacterial activity recommends R. capitata extract for further in vivo studies.

  8. BRAIN CHOLINESTERASE INHIBITION PRODUCED BY PROPOXUR AND DEPRESSION OF THE PHOTIC AFTER DISCHARGE OF FLASH EVOKED POTENTIALS IN LONG EVANS RATS.

    EPA Science Inventory

    Propoxur is a widely used N-methyl carbamate pesticide that acts by inhibiting cholinesterases (ChE), which may lead to cholinergic toxicity. Flash evoked potentials (FEPs) are a neurophysiological response following stimulation of the visual system with flashes of light. They ar...

  9. Cholinesterase inhibition of birds inhabiting wheat fields treated with methyl parathion and toxaphene

    USGS Publications Warehouse

    Niethammer, K.R.; Baskett, T.S.

    1983-01-01

    Red-winged blackbirds (Agelaius phoeniceus) and dickcissels (Spiza americana) inhabiting wheat fields treated with 0.67 kg AI/ha methyl parathion and 1.35 kg AI/ha toxaphene showed brain cholinesterase (ChE) inhibition compared with birds inhabiting untreated fields. Maximum inhibition occurred about five days after insecticide application. ChE activities again approached normal 10 days after treatment. ChE inhibition for dickcissels and red-winged blackbirds differed significantly (p<0.05); maximum inhibition for the former species was 74%, and for the latter, 40%. These differences could not be explained by the diets of the two species, as they were similar.

  10. The Leu-Arg-Glu (LRE) adhesion motif in proteins of the neuromuscular junction with special reference to proteins of the carboxylesterase/cholinesterase family.

    PubMed

    Johnson, Glynis; Moore, Samuel W

    2013-09-01

    Short linear motifs confer evolutionary flexibility on proteins as they can be added with relative ease allowing the acquisition of new functions. Such motifs may mediate a variety of signalling functions. The adhesion-mediating Leu-Arg-Glu (LRE) motif is enriched in laminin beta 2, and has been observed in other proteins, including members of the carboxylesterase/cholinesterase family. It acts as a stop signal for growing axons in the developing neuromuscular junction, binding to the voltage-gated calcium channel. In this bioinformatic analysis, we have investigated the presence of the motif in proteins of the neuromuscular junction, and have also examined its structural position and potential for ligand interaction, as well as phylogenetic conservation, in the carboxylesterase/cholinesterase family. The motif was observed to occur with a significantly higher frequency than expected in the UniProt/Swiss-Prot database, as well as in four individual species (human, mouse, Caenorhabditis elegans and Drosophila melanogaster). Examination of its presence in neuromuscular junction proteins showed it to be enriched in certain proteins of the synaptic basement membrane, including laminin, agrin, acetylcholinesterase and tenascin. A highly significant enrichment was observed in cytoskeletal proteins, particularly intermediate filament proteins and members of the spectrin family. In the carboxylesterase/cholinesterase family, the motif was observed in four conserved positions in the protein structure. It is present in the majority of mammalian acetylcholinesterases, as well as acetylcholinesterases from electric fish and a number of invertebrates. In insects, it is present in the ace-2, rather than in the synaptic ace-1, enzyme. It is also observed in the cholinesterase-like adhesion molecules (neuroligins, neurotactin and glutactin). It is never seen in butyrylcholinesterases, which do not mediate cell adhesion. In conclusion, the significant enrichment of the motif in

  11. Plasma Cholinesterase Activity in Female Green Turtles Chelonia mydas Nesting in Laguna de Terminos, Mexico Related to Organochlorine Pesticides in Their Eggs.

    PubMed

    Rivas-Hernández, Gerardo; May-Uc, Yaneli; Noreña-Barroso, Elsa; Cobos-Gasca, Víctor; Rodríguez-Fuentes, Gabriela

    2018-01-01

    The inhibition of cholinesterase (ChE) activity has been used as a biomarker of exposure to organophosphate and carbamate insecticides. ChE of nesting female green turtles (Chelonia mydas) were biochemically characterized using two substrates, acetylthiocholine iodide and butyrylthiocholine iodide, and three ChE inhibitors (eserine sulfate, BW284C51 and iso-OMPA). The results indicated that BChE is the predominant plasma ChE in female C. mydas, but with atypical properties that differ from those found in human BChE. Eggs from green turtles nesting at two sites in Laguna de Terminos contained µg g -1 (wet weight) quantities of organochlorine (OC) pesticides. Drins (aldrin, dieldrin, endrin, endrin ketone, endrin aldehyde) were found at the highest concentrations with no significant differences in the concentrations in eggs collected at the two sampling sites. A negative relationship was found between levels of OC pesticides in eggs and BChE activity in the plasma of female turtles laying the eggs. Since OC pesticides are not cholinesterase inhibitors, we hypothesized that this inverse relationship may be related to an antagonistic effect between OCs and organophosphate pesticides and mobilization of OCs from the fatty tissues of the female turtles into their eggs. However, further study is required to verify the hypothesis. It is also possible that other contaminants, such as petroleum hydrocarbons are responsible for the modulation of cholinesterase activity in female turtles.

  12. Recovery of cholinesterase activity in five avian species exposed to dicrotophos, an organophosphorus pesticide

    USGS Publications Warehouse

    Fleming, W.J.; Grue, C.E.

    1981-01-01

    The responses of brain and plasma cholinesterase (ChE) activities were examined in mallard ducks, bobwhite quail, barn owls, starlings, and common grackles given oral doses of dicrotophos, an organophosphorus insecticide. Up to an eightfold difference in response of brain ChE activity to dicrotophos was found among these species. Brain ChE activity recovered to within 2 SD of normal within 26 days after being depressed 55 to 64%. Recovery of brain ChE activity was similar among species and followed the model Y = a + b (log10X).

  13. New (benz)imidazolopyridino tacrines as nonhepatotoxic, cholinesterase inhibitors for Alzheimer disease.

    PubMed

    Boulebd, Houssem; Ismaili, Lhassane; Martin, Helene; Bonet, Alexandre; Chioua, Mourad; Marco Contelles, José; Belfaitah, Ali

    2017-05-01

    Due to the multifactorial nature of Alzheimer's disease, there is an urgent search for new more efficient, multitarget-directed drugs. This paper describes the synthesis, antioxidant and in vitro biological evaluation of ten (benz)imidazopyridino tacrines (7-16), showing less toxicity than tacrine at high doses, and potent cholinesterase inhibitory capacity, in the low micromolar range. Among them, compound 10 is a nonhepatotoxic tacrine at 1000 mM, showing moderate, but totally selective electric eel acetylcholinesterase inhibition, whereas molecule 16 is twofold less toxic than tacrine at 1000 μM, showing moderate and almost equipotent inhibition for electric eel acetylcholinesterase and equine butyrylcholinesterase. (Benz)imidazopyridino tacrines (7-16) have been identified as a new and promising type of tacrines for the potential treatment of Alzheimer's disease.

  14. [Interest of the cholinesterase assay during organophosphate poisonings].

    PubMed

    Jalady, A-M; Dorandeu, F

    2013-12-01

    Cholinesterases are the main targets of organophosphorus compounds. The two enzymes present in the blood (butyrylcholinesterase, BChE; acetylcholinesterase, AChE) are biomarkers of their systemic toxicity. Activity of the plasma BChE is very often determined as it allows a rapid diagnostic of poisoning and is a marker of the persistence of the toxicant in the blood. The activity of the red blood cell AChE gives a better picture of the synaptic inhibition in the nervous system but the assay is less commonly available in routine laboratories. Better biomarker of the exposure, it allows a diagnosis of the severity of the poisoning and helps to assess the efficacy of oxime therapy. Besides the practical aspects of blood collection and sample processing, and the interpretation of the assays, this review stresses the complementarity of both enzyme assays and recalls their crucial interest for the confirmation of poisoning with an organophosphorus in a situation of war or terrorist attack and for the monitoring of occupational exposures. Copyright © 2013. Published by Elsevier SAS.

  15. Studies on combined effects of organophosphates and heavy metals in birds. I. Plasma and brain cholinesterase in coturnix quail fed methyl mercury and orally dosed with parathion

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Dieter, M.P.; Ludke, J.L.

    1975-03-01

    It was found that mercury potentiated the toxicity and biochemical effects of parathion. Male Coturnix quail (Coturnix coturnix japonica) were fed a sublethal concentration of morsodren (4 ppm as methyl mercury) for 18 weeks. This resulted in an accumulation of 21.0 ppm of mercury in the liver and 8.4 ppm in the carcass. Birds fed clean feed and those fed morsodren-treated feed were orally dosed with 2, 4, 6, 8, and 10 mg/kg parathion, and their 48-h survival times compared. The computed LD/sub 50/ was 5.86 mg/kg in birds not fed morsodren and 4.24 in those fed the heavy metal.more » When challenged with a sublethal, oral dose of parathion (1.0 mg/kg), morsodren-fed birds exhibited significantly greater inhibition of plasma and brain cholinesterase activity than controls dosed with parathion. Brain cholinesterase activity was inhibited 41 percent in morsodren-fed birds and 26 percent in clean-fed birds dosed with parathion, which suggested that the increase in parathion toxicity in the presence of morsodren was directly related to the inhibition of brain cholinesterase. (auth)« less

  16. Toxicological Differences Between NMDA Receptor Antagonists and Cholinesterase Inhibitors.

    PubMed

    Shi, Xiaodong; Lin, Xiaotian; Hu, Rui; Sun, Nan; Hao, Jingru; Gao, Can

    2016-08-01

    Cholinesterase inhibitors (ChEIs), represented by donepezil, rivastigmine, and galantamine, used to be the only approved class of drugs for the treatment of Alzheimer's disease. After the approval of memantine by the Food and Drug Administration (FDA), N-methyl-d-aspartic acid (NMDA) receptor antagonists have been recognized by authorities and broadly used in the treatment of Alzheimer's disease. Along with complementary mechanisms of action, NMDA antagonists and ChEIs differ not only in therapeutic effects but also in adverse reactions, which is an important consideration in clinical drug use. And the number of patients using NMDA antagonists and ChEIs concomitantly has increased, making the matter more complicated. Here we used the FDA Adverse Event Reporting System for statistical analysis , in order to compare the adverse events of memantine and ChEIs. In general, the clinical evidence confirmed the safety advantages of memantine over ChEIs, reiterating the precautions of clinical drug use and the future direction of antidementia drug development. © The Author(s) 2016.

  17. BCHE and CYP2D6 genetic variation in Alzheimer's disease patients treated with cholinesterase inhibitors.

    PubMed

    Chianella, Caterina; Gragnaniello, Daniela; Maisano Delser, Pierpaolo; Visentini, Maria Francesca; Sette, Elisabetta; Tola, Maria Rosaria; Barbujani, Guido; Fuselli, Silvia

    2011-11-01

    Cholinesterase inhibitors are commonly prescribed to patients with Alzheimer's disease (AD) to enhance cholinergic neurotransmission. Differential response to these treatments has been observed, and claims have been made that individual genetic variants may influence the pharmacokinetic and pharmacodynamic properties of these drugs. Here we assess the effects of genetic variation at two loci involved in the activity of cholinesterase inhibitors on longitudinal clinical change in AD patients being treated with donepezil, galantamine, and rivastigmine. This was an open study in which 171 Italian AD patients treated with donepezil (n = 92), galantamine (n = 33), or rivastigmine (n = 46) were enrolled. Response to treatment was quantified by grading the patient's cognitive state (Mini-Mental State Examination) and the patient's ability to perform normal daily activities (Activities of Daily Living, Instrumental Activities of Daily Living) at baseline and after 6 and 12 months of treatment. Genetic variation was comprehensively characterized and analyzed at two loci: CYP2D6, which is involved in donepezil and galantamine metabolism, and BCHE, which codes for an enzyme (butyrylcholinesterase) which is both target and metabolizer of rivastigmine. APOE (coding for apolipoprotein E), which is associated with the risk of AD and inefficacy of specific AD treatments, was genotyped to control for patient stratification. The influence of the CYP2D6 and BCHE genotype on clinical changes after 12 months was evaluated by several tests of association. After 1 year of treatment, 29, 12, and 12 of the patients receiving donepezil, galantamine, and rivastigmine, respectively, showed a cognitive decrement, while eight patients interrupted the therapy before 12 months of treatment. No significant differences between the three treatments were observed in terms of response and tolerability. Non-responders show a higher proportion of BCHE and CYP2D6 mutated alleles, but

  18. Phytochemical profile of a blend of black chokeberry and lemon juice with cholinesterase inhibitory effect and antioxidant potential.

    PubMed

    Gironés-Vilaplana, Amadeo; Valentão, Patrícia; Andrade, Paula B; Ferreres, Federico; Moreno, Diego A; García-Viguera, Cristina

    2012-10-15

    In this study, black chokeberry concentrate was added (5% w/v) to lemon juice, since previous reports suggested potential health benefits of this blend. The phytochemical composition, antioxidant capacity (scavenging of DPPH, superoxide and hydroxyl radicals, and hypochlorous acid), and inhibitory activity against cholinesterase of the new blend were determined and compared with those of lemon juice and chokeberry in citric acid (5%). The chokeberry concentrate, rich in cyanidin-glycosides, quercetin derivatives, and 3-O-caffeoylquinic acid, and lemon juice, possessing flavones, flavanones, quercetin derivates, and hydroxycinnamic acids, were characterised. The new drink showed a higher antioxidant effect than the chokeberry or lemon controls for all the tested methods, except for hypochlorous acid, in which lemon juice displayed higher activity. Both the lemon juice and chokeberry controls inhibited acetylcholinesterase and butyrylcholinesterase, and this effect was increased in the new mixtures. The results of the different radical scavenging assays indicate that the lemon-black chokeberry (5% w/v) mixture was more antioxidative than the respective controls separately. Moreover, their inhibition of cholinesterase is of interest regarding neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, or senile dementia. Copyright © 2012 Elsevier Ltd. All rights reserved.

  19. Potent 3-Hydroxy-2-Pyridine Aldoxime Reactivators of Organophosphate-Inhibited Cholinesterases with Predicted Blood-Brain Barrier Penetration.

    PubMed

    Zorbaz, Tamara; Braïki, Anissa; Maraković, Nikola; Renou, Julien; de la Mora, Eugenio; Maček Hrvat, Nikolina; Katalinić, Maja; Silman, Israel; Sussman, Joel L; Mercey, Guillaume; Gomez, Catherine; Mougeot, Romain; Pérez, Belén; Baati, Rachid; Nachon, Florian; Weik, Martin; Jean, Ludovic; Kovarik, Zrinka; Renard, Pierre-Yves

    2018-04-19

    A new series of 3-hydroxy-2-pyridine aldoxime compounds have been designed, synthesised and tested in vitro, in silico, and ex vivo as reactivators of human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBChE) inhibited by organophosphates (OPs), for example, VX, sarin, cyclosarin, tabun, and paraoxon. The reactivation rates of three oximes (16-18) were determined to be greater than that of 2-PAM and comparable to that of HI-6, two pyridinium aldoximes currently used by the armies of several countries. The interactions important for a productive orientation of the oxime group within the OP-inhibited enzyme have been clarified by molecular-modelling studies, and by the resolution of the crystal structure of the complex of oxime 17 with Torpedo californica AChE. Blood-brain barrier penetration was predicted for oximes 15-18 based on their physicochemical properties and an in vitro brain membrane permeation assay. Among the evaluated compounds, two morpholine-3-hydroxypyridine aldoxime conjugates proved to be promising reactivators of OP-inhibited cholinesterases. Moreover, efficient ex vivo reactivation of phosphylated native cholinesterases by selected oximes enabled significant hydrolysis of VX, sarin, paraoxon, and cyclosarin in whole human blood, which indicates that the oximes have scavenging potential. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  20. In vitro cholinesterase inhibitory activity of some plants used in Iranian traditional medicine.

    PubMed

    Saeedi, Mina; Babaie, Khatereh; Karimpour-Razkenari, Elahe; Vazirian, Mahdi; Akbarzadeh, Tahmineh; Khanavi, Mahnaz; Hajimahmoodi, Mannan; Shams Ardekani, Mohammad Reza

    2017-11-01

    In this study, in vitro evaluation of cholinesterase inhibitory (ChEI) activity of various plants including betel nuts (Areca catechu L.), clove buds (Syzygium aromaticum L.), aerial parts of dodder (Cuscuta chinensis Lam.), common polypody rhizomes (Polypodium vulgare L.) and turpeth roots (Ipomoea turpethum R. Br.) which were recommended for the treatment of AD symptoms in Iranian Traditional Medicine (ITM) is reported. Among them, aqueous extract of A. catechu L. was found as the most potent anti-AChE (IC 50  = 32.00 μg/mL) and anti-BChE (IC 50  = 48.81 ± 0.1200 μg/mL) agent.

  1. Repeatability and validity of a field kit for estimation of cholinesterase in whole blood.

    PubMed Central

    London, L; Thompson, M L; Sacks, S; Fuller, B; Bachmann, O M; Myers, J E

    1995-01-01

    OBJECTIVES--To evaluate a spectrophotometric field kit (Test-Mate-OP) for repeatability and validity in comparison with reference laboratory methods and to model its anticipated sensitivity and specificity based on these findings. METHODS--76 farm workers between the age of 20 and 55, of whom 30 were pesticide applicators exposed to a range of organophosphates in the preceding 10 days, had blood taken for plasma cholinesterase (PCE) and erythrocyte cholinesterase (ECE) measurement by field kit or laboratory methods. Paired blinded duplicate samples were taken from subgroups in the sample to assess repeatability of laboratory and field kit methods. Field kits were also used to test venous blood in one subgroup. The variance obtained for the field kit tests was then applied to two hypothetical scenarios that used published action guidelines to model the kit's sensitivity and specificity. RESULTS--Repeatability for PCE was much poorer and for ECE slightly poorer than that of laboratory measures. A substantial upward bias for field kit ECE relative to laboratory measurements was found. Sensitivity of the kit to a 40% drop in PCE was 67%, whereas that for ECE was 89%. Specificity of the kit with no change in mean of the population was 100% for ECE and 91% for PCE. CONCLUSION--Field kit ECE estimation seems to be sufficiently repeatable for surveillance activities, whereas PCE does not. Repeatability of both tests seems to be too low for use in epidemiological dose-response investigations. Further research is indicated to characterise the upward bias in ECE estimation on the kit. PMID:7697143

  2. Secondary metabolites of Seseli rigidum: Chemical composition plus antioxidant, antimicrobial and cholinesterase inhibition activity.

    PubMed

    Stankov-Jovanović, V P; Ilić, M D; Mitić, V D; Mihajilov-Krstev, T M; Simonović, S R; Nikolić Mandić, S D; Tabet, J C; Cole, R B

    2015-01-01

    Extracts of different polarity obtained from various plant parts (root, leaf, flower and fruit) of Seseli rigidum were studied by different antioxidant assays: DPPH and ABTS radical scavenging activity, by total reducing power method as well as via total content of flavonoids and polyphenols. Essential oils of all plant parts showed weak antioxidant characteristics. The inhibitory concentration range of the tested extracts, against bacteria Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Bacillus cereus, and fungi Candida albicans and Aspergillus niger was 0.01-1.50 mg/mL and of a microbicidal 0.02-3.00 mg/mL. In the interaction with cholinesterase, all essential oils proved effective as inhibitors. The highest percentage of inhibition versus human and horse cholinesterase was shown by root essential oil (38.20% and 48.30%, respectively) among oils, and root hexane extract (40.56% and 50.65% respectively). Essential oils and volatile components of all plant parts were identified by GC, GC-MS and headspace/GC-MS. Statistical analysis of the ensemble of results showed that the root essential oil composition differed significantly from essential oils of other parts of the plant. Taking into account all of the studied activities, the root hexane extract showed the best overall properties. By means of high performance liquid chromatography coupled to high resolution mass spectrometry, the 30 most abundant constituents were identified in extracts of different polarity. The presence of identified constituents was linked to observed specific biological activities, thus designating compounds potentially responsible for each exhibited activity. Copyright © 2015 Elsevier B.V. All rights reserved.

  3. Expression of cholinesterase gene(s) in human brain tissues: translational evidence for multiple mRNA species.

    PubMed Central

    Soreq, H; Zevin-Sonkin, D; Razon, N

    1984-01-01

    To resolve the origin(s) of the molecular heterogeneity of human nervous system cholinesterases (ChEs), we used Xenopus oocytes, which produce biologically active ChE when microinjected with unfractionated brain mRNA. The RNA was prepared from primary gliomas, meningiomas and embryonic brain, each of which expresses ChE activity with distinct substrate specificities and molecular forms. Sucrose gradient fractionation of DMSO-denatured mRNA from these sources revealed three size classes of ChE-inducing mRNAs, sedimenting at approximately 32S, 20S and 9S. The amounts of these different classes of ChE-inducing mRNAs varied between the three tissue sources examined. To distinguish between ChEs produced in oocytes and having different substrate specificities, their activity was determined in the presence of selective inhibitors. Both 'true' (acetylcholine hydrolase, EC 3.1.1.7) and 'pseudo' (acylcholine acylhydrolase, EC 3.1.1.8) multimeric cholinesterase activities were found in the mRNA-injected oocytes. Moreover, human brain mRNAs inducing 'true' and 'pseudo' ChE activities had different size distribution, indicating that different mRNAs might be translated into various types of ChEs. These findings imply that the heterogeneity of ChEs in the human nervous system is not limited to the post-translational level, but extends to the level of mRNA. PMID:6745236

  4. Development of HuperTacrines as non-toxic, cholinesterase inhibitors for the potential treatment of Alzheimer's disease.

    PubMed

    Chioua, Mourad; Pérez, Marta; Bautista-Aguilera, Oscar M; Yañez, Matilde; López, Manuela G; Romero, Alejandro; Cacabelos, Ramón; de la Bellacasa, Raimon Puig; Brogi, Simone; Butini, Stefania; Borrell, José I; Marco-Contelles, Jose

    2015-01-01

    This paper describes our preliminary results on the ADMET, synthesis, biochemical evaluation, and molecular modeling of racemic HuperTacrines (HT), new hybrids resulting from the juxtaposition of huperzine A and tacrine for the potential treatment of Alzheimer's disease (AD). The synthesis of these HT was executed by Friedländer-type reactions of 2-amino-6-oxo-1,6-dihydropyridine-3-carbonitriles, or 7-amino-2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridine- 8-carbonitriles, with cyclohexanone. In the biochemical evaluation, initial and particular attention was devoted to test their toxicity on human hepatoma cells, followed by the in vitro inhibition of human cholinesterases (hAChE, and hBuChE), and the kinetics/mechanism of the inhibition of the most potent HT; simultaneous molecular modeling on the best HT provided the key binding interactions with the human cholinesterases. >From these analyses, (±)-5-amino-3-methyl- 3,4,6,7,8,9-hexahydrobenzo[b][1,8]naphthyridin-2(1H)-one (HT1) and (±)-5-amino-3-(2,6-dichlorophenyl)-3,4,6,7,8,9- hexahydrobenzo[b][1,8]naphthyridin-2(1H)-one (HT3) have emerged as characterized by extremely low liver toxicity reversible mixed-type, selective hAChE and, quite selective irreversible hBuChEIs, respectively, showing also good druglike properties for AD-targeted drugs.

  5. HPTLC Fingerprinting and Cholinesterase Inhibitory and Metal-Chelating Capacity of Various Citrus Cultivars and
Olea europaea

    PubMed Central

    Senol, Fatma Sezer; Ankli, Anita; Reich, Eike

    2016-01-01

    Summary Inhibitory activity of thirty-one ethanol extracts obtained from albedo, flavedo, seed and leaf parts of 17 cultivars of Citrus species from Turkey, the bark and leaves of Olea europaea L. from two locations (Turkey and Cyprus) as well as caffeic acid and hesperidin was tested against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), related to the pathogenesis of Alzheimer’s disease, using ELISA microtiter assays at 500 µg/mL. Metal-chelating capacity of the extracts was also determined. BChE inhibitory effect of the Citrus sp. extracts was from (7.7±0.7) to (70.3±1.1) %, whereas they did not show any inhibition against AChE. Cholinesterase inhibitory activity of the leaf and bark ethanol extracts of O. europaea was very weak ((10.2±3.1) to (15.0±2.3) %). The extracts had either no or low metal-chelating capacity at 500 µg/mL. HPTLC fingerprinting of the extracts, which indicated a similar phytochemical pattern, was also done using the standards of caffeic acid and hesperidin with weak cholinesterase inhibition. Among the screened extracts, the albedo extract of C. limon ‘Interdonato’, the flavedo extracts of ‘Kara Limon’ and ‘Cyprus’ cultivars and the seed extract of C. maxima appear to be promising as natural BChE inhibitors. PMID:27956858

  6. A randomised controlled study of the effect of cholinesterase inhibition on colon function in patients with diabetes mellitus and constipation

    PubMed Central

    Bharucha, Adil E; Low, Phillip; Camilleri, Michael; Veil, Erica; Burton, Duane; Kudva, Yogish; Shah, Pankaj; Gehrking, Tonette; Zinsmeister, Alan R

    2014-01-01

    Objectives Chronic constipation in diabetes mellitus is associated with colonic motor dysfunction and is managed with laxatives. Cholinesterase inhibitors increase colonic motility. This study evaluated the effects of a cholinesterase inhibitor on gastrointestinal and colonic transit and bowel function in diabetic patients with constipation. Design After a 9-day baseline period, 30 patients (mean±SEM age 50±2 years) with diabetes mellitus (18 type 1, 12 type 2) and chronic constipation without defaecatory disorder were randomised to oral placebo or pyridostigmine, starting with 60 mg three times a day, increasing by 60 mg every third day up to the maximum tolerated dose or 120 mg three times a day; this dose was maintained for 7 days. Gastrointestinal and colonic transit (assessed by scintigraphy) and bowel function were evaluated at baseline and the final 3 and 7 days of treatment, respectively. Treatment effects were compared using analysis of covariance, with gender, body mass index and baseline colonic transit as covariates. Results 19 patients (63%) had moderate or severe autonomic dysfunction; 16 (53%) had diabetic retinopathy. 14 of 16 patients randomised to pyridostigmine tolerated 360 mg daily; two patients took 180 mg daily. Compared with placebo (mean±SEM 1.98±0.17 (baseline), 1.84±0.16 (treatment)), pyridostigmine accelerated (1.96±0.18 (baseline), 2.45±0.2 units (treatment), p<0.01) overall colonic transit at 24 h, but not gastric emptying or small-intestinal transit. Treatment effects on stool frequency, consistency and ease of passage were significant (p≤0.04). Cholinergic side effects were somewhat more common with pyridostigmine (p=0.14) than with placebo. Conclusions Cholinesterase inhibition with oral pyridostigmine accelerates colonic transit and improves bowel function in diabetic patients with chronic constipation. Clinical trial registration number TrialRegNo (NCT 00276406). PMID:22677718

  7. Cholinesterase inhibitory, anti-amyloidogenic and neuroprotective effect of the medicinal plant Grewia tiliaefolia - An in vitro and in silico study.

    PubMed

    Sheeja Malar, Dicson; Beema Shafreen, Rajamohamed; Karutha Pandian, Shunmugiah; Pandima Devi, Kasi

    2017-12-01

    Grewia tiliaefolia Vahl. (Tiliaceae) is a sub-tropical plant used as an indigenous medicine in India. However, its efficacy has not been evaluated against Alzheimer's disease. The objective of this study is to evaluate cholinesterase inhibitory, anti-aggregation and neuroprotective activity of G. tiliaefolia. Grewia tiliaefolia leaves were collected from Eastern Ghats region, India, and subjected to successive extraction (petroleum ether, chloroform, ethyl acetate, methanol and water). The extracts were subjected to in vitro antioxidant, anticholinesterase and anti-aggregation assays. The active methanol extract (MEGT) was separated using column chromatography. LC-MS analysis was done and the obtained compounds were docked against acetylcholinesterase (AChE) enzyme to identify the active component. Antioxidant assays demonstrated that the MEGT showed significant free radical scavenging activity at the IC 50 value of 71.5 ± 1.12 μg/mL. MEGT also exhibited significant dual cholinesterase inhibition with IC 50 value of 64.26 ± 2.56 and 54 ± 0.7 μg/mL for acetyl and butyrylcholinesterase (BChE), respectively. Also, MEGT showed significant anti-aggregation activity by preventing the oligomerization of Aβ 25-35 . Further, MEGT increased the viability of Neuro2a cells up to 95% against Aβ 25-35 neurotoxicity. LC-MS analysis revealed the presence of 16 compounds including vitexin, ellagic acid, isovitexin, etc. In silico analysis revealed that vitexin binds effectively with AChE through strong hydrogen bonding. These results were further confirmed by evaluating the activity of vitexin in vitro, which showed dual cholinesterase inhibition with IC 50 value of 15.21 ± 0.41 and 19.75 ± 0.16 μM for acetyl and butyrlcholinesterase, respectively. Grewia tiliaefolia can be considered as a promising therapeutic agent for the treatment of AD.

  8. Serum cholinesterase variants in African leprosy patients resident in Rhodesia.

    PubMed

    Whittaker, M; Lowe, R F; Ellis, B P

    1976-01-01

    Blood samples from 580 African leprosy patients living in Rhodesia have been phenotyped for the plasma cholinesterase variants. The Africans have been grouped according to country of origin and tribal affiliation. We have found no individual with an Ea1 gene and are unable to resolve the contradictory evidence for an association between this gene and leprosy. The frequency of the Ef1 gene is higher than that usually found in Caucasian populations, being 0.046 in lepromatous leprosy patients and similar to the 0.056 found in healthy African controls. In tuberculoid leprosy patients the frequency is, however, significantly lower at 0.019. On the other hand, the frequency of the C5+ variant is essentially the same for the tuberculoid leprosy patients and the healthy controls (4%) while for the lepromatous leprosy patients it is about 7% approaching the 10-15% found in many Caucasian populations.

  9. Risk Factors for Nursing Home Placement in Alzheimer's Disease: A Longitudinal Study of Cognition, ADL, Service Utilization, and Cholinesterase Inhibitor Treatment

    ERIC Educational Resources Information Center

    Wattmo, Carina; Wallin, Asa K.; Londos, Elisabet; Minthon, Lennart

    2011-01-01

    Purpose of the Study: To identify risk factors for early nursing home placement (NHP) in Alzheimer's disease (AD), focusing on the impact of longitudinal change in cognition, activities of daily living (ADL), service utilization, and cholinesterase inhibitor treatment (ChEI). Design and Methods: In an open, 3-year, prospective, multicenter study…

  10. Cholinesterases: structure of the active site and mechanism of the effect of cholinergic receptor blockers on the rate of interaction with ligands

    NASA Astrophysics Data System (ADS)

    Antokhin, A. M.; Gainullina, E. T.; Taranchenko, V. F.; Ryzhikov, S. B.; Yavaeva, D. K.

    2010-10-01

    Modern views on the structure of cholinesterase active sites and the mechanism of their interaction with organophosphorus inhibitors are considered. The attention is focused on the mechanism of the effect of cholinergic receptor blockers, acetylcholine antagonists, on the rate of interaction of acetylcholine esterase with organophosphorus inhibitors.

  11. [Phosphoric acid ester preparations used in cattle, swine and sheep with special reference to cholinesterase activity. 4. Use of phosphoric acid esters and their effect on acetylcholinesterase activity in sheep].

    PubMed

    Mieth, K; Beier, D; Losch, K

    1975-01-01

    The use of organophosphorus preparations for the control of ectoparasites and endoparasites of sheep, particularly systemic application, is discussed. Experiments on 13 groups of sheep with five preparations produced in the German Democratic Republic in various formulations and concentrations showed that external application had good contact activity, but little was absorbed. Acetylcholinesterase activity was not inhibited, except by pour-on application of doses several times the normal dose. The preparations were arranged in order of cholinesterase inhibition. In contrast to cattle, diminished cholinesterase activity was unreliable as in indicator of systemic toxicity of organophosphorus preparations in sheep.

  12. Brain cholinesterase activity of apparently normal wild birds

    USGS Publications Warehouse

    Hill, E.F.

    1988-01-01

    Organophosphorus and carbamate pesticides are potent anticholinesterase substances that have killed large numbers of wild birds of various species. Cause of death is diagnosed by demonstration of depressed brain cholinesterase (ChE) activity in combination with chemical detection of anticholinesterase residue in the affected specimen. ChE depression is determined by comparison of the affected specimen to normal ChE activity for a sample of control specimens of the same species, but timely procurement of controls is not always possible. Therefore, a reference file of normal whole brain ChE activity is provided for 48 species of wild birds from North America representing 11 orders and 23 families for use as emergency substitutes in diagnosis of anticholinesterase poisoning. The ChE values, based on 83 sets of wild control specimens from across the United States, are reproducible provided the described procedures are duplicated. Overall, whole brain ChE activity varied nearly three-fold among the 48 species represented, but it was usually similar for closely related species. However, some species were statistically separable in most families and some species of the same genus differed as much as 50%.

  13. Symptoms and cholinesterase activity among rural residents living near cotton fields in Nicaragua.

    PubMed Central

    Keifer, M; Rivas, F; Moon, J D; Checkoway, H

    1996-01-01

    OBJECTIVES: To explore whether symptoms resulted from pesticide spray drift on residentially exposed populations in rural Nicaragua. METHODS: 100 residents, each 10 years of age or older, were randomly selected from a Nicaraguan community surrounded by actively sprayed cotton fields (the exposed community) and from a socioeconomically similar community far from agricultural spraying (the control community). Subjects working with pesticides were excluded, and the study was conducted at the end of the 1990 cotton spraying season (August-December). Demographic information, exposure questions, and prevalence of 11 acute symptoms and 17 chronic symptoms were gathered from a structured interview. Finger stick erythrocyte cholinesterase (AChE) was measured with a portable colorimeter. Acute symptoms were grouped according to their previously known associations with cholinesterase (ChE) inhibitors into four ordinal categories (asymptomatic, non-specific, possible, probable). RESULTS: Residents from the exposed community were significantly more likely to report recently sighting a spray plane near their community, exposure to pesticide from drift, crossing recently sprayed fields, eating home grown food, and feeling ill after drift exposure. The mean AChE value was significantly lower for residents of the exposed community (4.9 v 5.3 IU/dl). The proportion of subjects complaining of one or more chronic or acute symptoms was significantly higher for the exposed community (87%) than for the controls (53%). Odds ratios for residents in the exposed community, by symptom categories, were non-specific 1.6 (95% confidence interval (95% CI) 0-8 to 3.2), possible 4.1 (95% CI 1.7 to 10.2), and probable 9.93 (95% CI 2-9 to 34.4). CONCLUSION: These findings indicate a strong association between exposure to aerial pesticides and symptoms. This study should be replicated with more quantitative exposure measures, for if confirmed, the results have relevance for millions in rural

  14. Plasma cholinesterase studies on south-eastern Bantu of Mozambique.

    PubMed

    Whittaker, M; Reys, L

    1975-01-01

    Blood samples from four Bantu tribes in South-East Mozambique have been phenotyped for the plasma cholinesterase variants of the E1 locus. A control roup of 153 Portuguese residents in Mozambique have also been phenotyped. The frequencies of both the E1a and E1f genes in the Portuguese population is very similar to those in other Caucasian populations. The absence of the E1a gene in the four Bantu tribes provides more evidence of the rarity of this gene in Negroid populations. There is an increased frequency of E1f gene in all tribes as compared with previous surveys. The Ronga and Bitonga tribes have similar E1f frequencies of 0.047 and 0.048, respectively. The Shangana has an E1f frequency of 0.060, and the corresponding figure for the Chopi tribe is 0.089. The latter is the highest recorded frequency for this gene. The results give some support to the doubts concerning the affiliation of the Chopi tribe.

  15. Cholinesterase inhibitors may increase phosphorylated tau in Alzheimer’s disease

    PubMed Central

    Wilcock, Gordon K.; Vinters, Harry V.; Perry, Elaine K.; Perry, Robert; Ballard, Clive G.; Love, Seth

    2014-01-01

    Cholinesterase inhibitors (ChEIs) are widely used for the symptomatic treatment of Alzheimer’s disease (AD). In vitro and in animal studies, ChEIs have been shown to influence the processing of Aβ and the phosphorylation of tau, proteins that are the principal constituents of the plaques and neurofibrillary tangles, respectively, in AD brain. However, little is known about the effects of these drugs on Aβ and tau pathology in AD. Using avidin-biotin immunohistochemistry and computer-assisted image analysis, we compared Aβ and tau loads in the frontal and temporal cortices of 72 brains from matched cohorts of AD patients who had or had not received ChEIs. Patients treated with ChEIs had accumulated significantly more phospho-tau in their cerebral cortex than had untreated patients (P = 0.004). Aβ accumulation was reduced but not significantly. These data raise the possibility that increased tau phosphorylation may influence long-term clinical responsiveness to ChEIs. PMID:19240967

  16. Computer simulation of the active site of human serum cholinesterase

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Kefang Jiao; Song Li; Zhengzheng Lu

    1996-12-31

    The first 3D-structure of acetylchelinesterase from Torpedo California electric organ (T.AChE) was published by JL. Sussman in 1991. We have simulated 3D-structure of human serum cholinesterase (H.BuChE) and the active site of H.BuChE. It is discovered by experiment that the residue of H.BuChE is still active site after a part of H.BuChE is cut. For example, the part of 21KD + 20KD is active site of H.BuChE. The 20KD as it is. Studies on these peptides by Hemelogy indicate that two active peptides have same negative electrostatic potential maps diagram. These negative electrostatic areas attached by acetyl choline with positivemore » electrostatic potency. We predict that 147...236 peptide of AChE could be active site because it was as 20KD as with negative electrostatic potential maps. We look forward to proving from other ones.« less

  17. Piper betle leaves: profiling phenolic compounds by HPLC/DAD-ESI/MS(n) and anti-cholinesterase activity.

    PubMed

    Ferreres, Federico; Oliveira, Andreia P; Gil-Izquierdo, Angel; Valentão, Patrícia; Andrade, Paula B

    2014-01-01

    Piper betle L. is a widely distributed plant in the tropical and subtropical regions, its leaves being largely consumed as a masticator and mouth freshener. The purposes of this work were to characterise the phenolic profile of this species and to improve knowledge of its anti-cholinesterase properties. The phenolic composition of P. betle leaf aqueous and ethanol extracts was characterised by HPLC coupled with a diode-array detector and combined with electrospray ionisation tandem MS, and in vitro cholinesterase inhibitory capacity of both extracts was assessed by spectrophotometric microassays. The effect on neuronal cells (SH-SY5Y) viability was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction and lactate dehydrogenase leakage. Twelve phenolic compounds, comprising a phenylpropanoid, five cinnamoyl and six flavonoids derivatives were identified in P. betle leaves. Hydroxychavicol was the major compound in both extracts; however, the aqueous extract presented a greater diversity of compounds. Both extracts showed strong activity against both acetyl- and butyrylcholinesterase, which can be due, at least partially, to the phenolic composition. Furthermore, the aqueous extract proved to be cytotoxic to human neuroblastoma cells at concentrations higher than 500 µg/mL. The results suggest that the consumption of P. betle leaves as an infusion can have a positive impact in the prevention and treatment of neurodegenerative diseases. Apigenin and luteolin derivatives are reported for the first time in this species. Copyright © 2014 John Wiley & Sons, Ltd.

  18. Interactions between scopolamine and muscarinic cholinergic agonists or cholinesterase inhibitors on spatial alternation performance in rats.

    PubMed

    Shannon, H E; Bemis, K G; Hendrix, J C; Ward, J S

    1990-12-01

    The effects on working memory of the muscarinic cholinergic agonists oxotremorine, arecoline, RS86 and pilocarpine, and the cholinesterase inhibitors physostigmine and tetrahydroaminoacadine were investigated in male F344 rats. Working memory was assessed by behavior maintained under a spatial alternation schedule of food presentation in which the interval between trials was varied from 2 to 32 sec. Under control conditions the percentage of correct responses decreased as the retention interval was varied from 2 to 32 sec. Administered alone the cholinergic agonists oxotremorine (0.01-0.1 mg/kg), arecoline (3-30 mg/kg), RS86 (0.3-3 mg/kg) and pilocarpine (0.3-3.0 mg/kg), and the cholinesterase inhibitors physostigmine (0.01-0.1 mg/kg) and tetrahydroaminoacridine (0.3-3.0 mg/kg) either had no effect on or produced dose-related deficits in working memory and decreases in response rates. The muscarinic antagonist scopolamine (0.1 mg/kg) produced retention interval-dependent decreases in the percentage of correct responding and rates of responding. The cholinergic agonists and tetrahydroaminoacridine failed to reverse the effects of scopolamine. However, physostigmine produced a dose-dependent reversal of the working-memory deficits and response-rate decreasing effects of scopolamine. The present results are consistent with the interpretation that drugs which primarily enhance M2 muscarinic cholinergic transmission are ineffective in enhancing working memory or in reversing scopolamine-induced deficits in working memory.

  19. DEPRESSION OF THE PHOTIC AFTER DISCHARGE OF FLASH EVOKED POTENTIALS BY PHYSOSTIGMINE, CARBARYL AND PROPOXUR AND THE RELATIONSHIP TO INHIBITION OF BRAIN CHOLINESTERASE

    EPA Science Inventory

    The effects of N-methyl carbamate pesticides on the photic after discharge (PhAD) of flash evoked potentials (FEPs) and the relationship between inhibition of brain cholinesterase (ChE) activity and the PhAD were evaluated. FEPs were recorded in Long Evans rats treated with physo...

  20. Development of organophosphate hydrolase activity in a bacterial homolog of human cholinesterase

    NASA Astrophysics Data System (ADS)

    Legler, Patricia; Boisvert, Susanne; Compton, Jaimee; Millard, Charles

    2014-07-01

    We applied a combination of rational design and directed evolution (DE) to Bacillus subtilis p-nitrobenzyl esterase (pNBE) with the goal of enhancing organophosphorus acid anhydride hydrolase (OPAAH) activity. DE started with a designed variant, pNBE A107H, carrying a histidine homologous with human butyrylcholinesterase G117H to find complementary mutations that further enhance its OPAAH activity. Five sites were selected (G105, G106, A107, A190, and A400) within a 6.7 Å radius of the nucleophilic serine O?. All 95 variants were screened for esterase activity with a set of five substrates: pNP-acetate, pNP-butyrate, acetylthiocholine, butyrylthiocholine, or benzoylthiocholine. A microscale assay for OPAAH activity was developed for screening DE libraries. Reductions in esterase activity were generally concomitant with enhancements in OPAAH activity. One variant, A107K, showed an unexpected 7-fold increase in its kcat/Km for benzoylthiocholine, demonstrating that it is also possible to enhance the cholinesterase activity of pNBE. Moreover, DE resulted in at least three variants with modestly enhanced OPAAH activity compared to wild type pNBE. A107H/A190C showed a 50-fold increase in paraoxonase activity and underwent a slow time- and temperature-dependent change affecting the hydrolysis of OPAA and ester substrates. Structural analysis suggests that pNBE may represent a precursor leading to human cholinesterase and carboxylesterase 1 through extension of two vestigial specificity loops; a preliminary attempt to transfer the Ω-loop of BChE into pNBE is described. pNBE was tested as a surrogate scaffold for mammalian esterases. Unlike butyrylcholinesterase and pNBE, introducing a G143H mutation (equivalent to G117H) did not confer detectable OP hydrolase activity on human carboxylesterase 1. We discuss the importance of the oxyanion-hole residues for enhancing the OPAAH activity of selected serine hydrolases.

  1. Cholinesterase Inhibition and Depression of the Photic After Discharge of Flash Evoked Potentials Following Acute or Repeated Exposures to a Mixture of Carbaryl and Propoxur

    EPA Science Inventory

    While information exists regarding inhibition of cholinesterase (ChE) activity, little is known about neurophysiological changes produced by a mixture of N-methyl carbamate pesticides. Previously, we reported that acute treatment with propoxur or carbaryl decreased the duration o...

  2. Cholinesterase activity in the cup oyster Saccostrea sp. exposed to chlorpyrifos, imidacloprid, cadmium and copper.

    PubMed

    Moncaleano-Niño, Angela M; Luna-Acosta, Andrea; Gómez-Cubillos, Maria Camila; Villamil, Luisa; Ahrens, Michael J

    2018-04-30

    In the present study, the sensitivity and concentration dependence of three functionally-defined components of cholinesterase activity (total: T-ChE; eserine-sensitive: Es-ChE; and eserine-resistant: Er-ChE) were quantified in the gill, digestive gland and adductor muscle of the tropical cup oyster Saccostrea sp., following acute (96h) aqueous exposure to commercial formulations of the organophosphate (OP) insecticide chlorpyrifos and the neonicotinoid (NN) imidacloprid (concentration range: 0.1-100mg/L), as well as to dissolved cadmium and copper (concentration range: 1-1000μg/L). Oysters (1.5-5.0cm shell length), field-collected from a boating marina in Santa Marta, Colombia (Caribbean Sea) were exposed in the laboratory to each substance at five concentrations. T-ChE, Es-ChE, and Er-ChE activity were quantified in the three tissues in pools of 5 individuals (3 replicates per concentration), before and after inhibition with the total cholinesterase inhibitor eserine (physostigmine, 100µM). Oysters exposed to chlorpyrifos, imidacloprid and Cd showed reduced T-ChE and Es-ChE activity in gills at highest exposure concentrations, with Es-ChE activity being inhibited proportionally more so than T-ChE, whereas Er-ChE activity showed no significant concentration-response. Digestive gland also showed diminished T-ChE, Es-ChE and Er-ChE activity for highest chlorpyrifos and Cd concentrations relative to controls, but an increase of T-ChE and Er-ChE activity at the highest imidacloprid concentration (100mg/L). For Cu, T-ChE, Es-ChE and Er-ChE activities in gills and digestive gland were elevated relative to controls in oysters exposed to Cu concentrations > 100µg/L. In adductor muscle, T-ChE, Es-ChE and Er-ChE activity showed no apparent pattern for any of the four xenobiotics and concentration levels tested. Although this study confirms acute (96h) concentration-dependent reduction of tissue T-ChE and Es-ChE activity in gills and digestive glands of Saccostrea sp

  3. Reactivation of model cholinesterases by oximes and intermediate phosphyloximes: A computational study

    PubMed Central

    Vyas, Shubham; Hadad, Christopher M.

    2008-01-01

    Phosphyloximes (POX) are generated upon the reactivation of organophosphorus (OP) inhibited cholinesterases (ChEs) by pyridinium oximes. These POXs are known to be potent inhibitors of the ChEs following reactivation. However, they can also decompose to give an OP derivative and a cyano derivative of the oxime when a base abstracts the benzylic proton. Using density functional theory, thermodynamic properties were calculated for the reactivation and decomposition pathways of three different oximes (2-PAM, 3-PAM and 4-PAM) with six different OPs (cyclosarin, paraoxon, sarin, tabun, VR and VX). For reactivation purposes, 2-PAM is predicted to be more efficient than 3- and 4-PAM. Based on atomic charges and relative energies, 2-POXs were found to be more inclined towards the decomposition process. PMID:18582852

  4. Antioxidant activity and cholinesterase inhibition studies of four flavouring herbs from Alentejo.

    PubMed

    Arantes, Sílvia; Piçarra, Andreia; Candeias, Fátima; Caldeira, A Teresa; Martins, M Rosário; Teixeira, Dora

    2017-09-01

    Essential oils (EOs) and aqueous extracts of aerial parts of four aromatic species, Calamintha nepeta, Foeniculum vulgare, Mentha spicata and Thymus mastichina, from southwest of Portugal were characterised chemically and analysed in order to evaluate their antioxidant potential and cholinesterase inhibitory activities. The main components of EOs were oxygenated monoterpenes, and aqueous extracts were rich in phenol and flavonoid compounds. EOs and aqueous extracts presented a high antioxidant potential, with ability to protect the lipid substrate, free radical scavenging and iron reducing power. Furthermore, EOs and extracts showed AChE and BChE inhibitory activities higher than rivastigmine, the standard drug. Results suggested the potential use of EOs and aqueous extracts of these flavouring herbs as nutraceutical or pharmaceutical preparations to minimise the oxidative stress and the progression of degenerative diseases.

  5. Cholinesterase inhibition reduces arrhythmias in asymptomatic Chagas disease.

    PubMed

    Castro, Renata R T; Porphirio, Graciema; Xavier, Sergio S; Moraes, Ruy S; Ferlin, Elton L; Ribeiro, Jorge P; da Nóbrega, Antonio C L

    2017-10-01

    Parasympathetic dysfunction may play a role in the genesis of arrhythmias in Chagas disease. This study evaluates the acute effects of pyridostigmine (PYR), a reversible cholinesterase inhibitor, on the occurrence of arrhythmias in patients with Chagas cardiac disease. Following a double-blind, randomized, placebo-controlled, cross-over protocol, 17 patients (age 50±2 years) with Chagas cardiac disease type B underwent 24-hour Holter recordings after oral administration of either pyridostigmine bromide (45 mg, 3 times/day) or placebo (PLA). Pyridostigmine reduced the 24-hours incidence (median [25%-75%]) of premature ventricular beats-PLA: 2998 (1920-4870), PYR: 2359 (940-3253), P=.044; ventricular couplets-PLA: 84 (15-159), PYR: 33 (6-94), P=.046. Although the total number of nonsustained ventricular tachycardia in the entire group was not different (P=.19) between PLA (1 [0-8]) and PYR (0 [0-4]), there were fewer episodes under PYR in 72% of the patients presenting this type of arrhythmia (P=.033). Acute administration of pyridostigmine reduced the incidence of nonsustained ventricular arrhythmias in patients with Chagas cardiac disease. Further studies that address the use of pyridostigmine by patients with Chagas cardiac disease under a more prolonged follow-up are warranted. © 2017 John Wiley & Sons Ltd.

  6. Reactivation of VX-inhibited cholinesterase by 2-PAM and HS-6 in rats.

    PubMed

    Harris, L W; Stitcher, D L

    1983-01-01

    Atropinized rats intoxicated with ethyl-S-2-diisopropyl aminoethyl methyl phosphonothioate (VX), 15 mg/kg iv, were divided into three groups and were treated with normal saline, iv, 30 mg/kg of 2-PAM C1, iv, and 30 mg/kg of HS-6, iv. One hr after administration of therapy they were decapitated and cholinesterase (ChE) activity was determined on blood, brain and diaphragm tissue. Both 2-PAM C1 and HS-6 markedly reactivated VX-inhibited blood and diaphragm ChE. Brain ChE activity was not significantly reactivated by either oxime. The effectiveness of these oximes in restoration of VX-inactivated ChE in vivo offers an explanation as to why conventional atropine/oxime therapy is so effective against VX intoxication.

  7. Synthesis, characterization, X-ray crystallography, acetyl cholinesterase inhibition and antioxidant activities of some novel ketone derivatives of gallic hydrazide-derived Schiff bases.

    PubMed

    Gwaram, Nura Suleiman; Ali, Hapipah Mohd; Abdulla, Mahmood Ameen; Buckle, Michael J C; Sukumaran, Sri Devi; Chung, Lip Yong; Othman, Rozana; Alhadi, Abeer A; Yehye, Wageeh A; Hadi, A Hamid A; Hassandarvish, Pouya; Khaledi, Hamid; Abdelwahab, Siddig Ibrahim

    2012-02-28

    Alzheimer's disease (AD) is the most common form of dementia among older people and the pathogenesis of this disease is associated with oxidative stress. Acetylcholinesterase inhibitors with antioxidant activities are considered potential treatments for AD. Some novel ketone derivatives of gallic hydrazide-derived Schiff bases were synthesized and examined for their antioxidant activities and in vitro and in silico acetyl cholinesterase inhibition. The compounds were characterized using spectroscopy and X-ray crystallography. The ferric reducing antioxidant power (FRAP) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) assays revealed that all the compounds have strong antioxidant activities. N-(1-(5-bromo-2-hydroxyphenyl)-ethylidene)-3,4,5-trihydroxybenzohydrazide (2) was the most potent inhibitor of human acetyl cholinesterase, giving an inhibition rate of 77% at 100 μM. Molecular docking simulation of the ligand-enzyme complex suggested that the ligand may be positioned in the enzyme's active-site gorge, interacting with residues in the peripheral anionic subsite (PAS) and acyl binding pocket (ABP). The current work warrants further preclinical studies to assess the potential for these novel compounds for the treatment of AD.

  8. Kinetic parameters of cholinesterase interactions with organophosphates: retrieval and comparison tools available through ESTHER database: ESTerases, alpha/beta Hydrolase Enzymes and Relatives.

    PubMed

    Chatonnet, A; Hotelier, T; Cousin, X

    1999-05-14

    Cholinesterases are targets for organophosphorus compounds which are used as insecticides, chemical warfare agents and drugs for the treatment of disease such as glaucoma, or parasitic infections. The widespread use of these chemicals explains the growing of this area of research and the ever increasing number of sequences, structures, or biochemical data available. Future advances will depend upon effective management of existing information as well as upon creation of new knowledge. The ESTHER database goal is to facilitate retrieval and comparison of data about structure and function of proteins presenting the alpha/beta hydrolase fold. Protein engineering and in vitro production of enzymes allow direct comparison of biochemical parameters. Kinetic parameters of enzymatic reactions are now included in the database. These parameters can be searched and compared with a table construction tool. ESTHER can be reached through internet (http://www.ensam.inra.fr/cholinesterase). The full database or the specialised X-window Client-server system can be downloaded from our ftp server (ftp://ftp.toulouse.inra.fr./pub/esther). Forms can be used to send updates or corrections directly from the web.

  9. Occupational determinants of serum cholinesterase inhibition among organophosphate-exposed agricultural pesticide handlers in Washington State

    PubMed Central

    Hofmann, Jonathan N; Keifer, Matthew C; De Roos, Anneclaire J; Fenske, Richard A; Furlong, Clement E; van Belle, Gerald; Checkoway, Harvey

    2010-01-01

    Objective To identify potential risk factors for serum cholinesterase (BuChE) inhibition among agricultural pesticide handlers exposed to organophosphate (OP) and N-methyl-carbamate (CB) insecticides. Methods We conducted a longitudinal study among 154 agricultural pesticide handlers who participated in the Washington State cholinesterase monitoring program in 2006 and 2007. BuChE inhibition was analyzed in relation to reported exposures before and after adjustment for potential confounders using linear regression. Odds ratios estimating the risk of ‘BuChE depression’ (>20% from baseline) were also calculated for selected exposures based on unconditional logistic regression analyses. Results An overall decrease in mean BuChE activity was observed among study participants at the time of follow-up testing during the OP/CB spray season relative to pre-season baseline levels (mean decrease of 5.6%, P < 0.001). Score for estimated cumulative exposure to OP/CB insecticides in the past 30 days was a significant predictor of BuChE inhibition (β = −1.74, P < 0.001). Several specific work practices and workplace conditions were associated with greater BuChE inhibition, including mixing/loading pesticides and cleaning spray equipment. Factors that were protective against BuChE inhibition included full-face respirator use, wearing chemical-resistant boots, and storing personal protective equipment in a locker at work. Conclusions Despite existing regulations, agricultural pesticide handlers continue to be exposed to OP/CB insecticides at levels resulting in BuChE inhibition. These findings suggest that modifying certain work practices could potentially reduce BuChE inhibition. Replication from other studies will be valuable. PMID:19819864

  10. Cholinesterase activity of muscle tissue from freshwater fishes: characterization and sensitivity analysis to the organophosphate methyl-paraoxon.

    PubMed

    Lopes, Renato Matos; Filho, Moacelio Veranio Silva; de Salles, João Bosco; Bastos, Vera Lúcia Freire Cunha; Bastos, Jayme Cunha

    2014-06-01

    The biochemical characterization of cholinesterases (ChE) from different teleost species has been a critical step in ensuring the proper use of ChE activity levels as biomarkers in environmental monitoring programs. In the present study, ChE from Oreochromis niloticus, Piaractus mesopotamicus, Leporinus macrocephalus, and Prochilodus lineatus was biochemically characterized by specific substrates and inhibitors. Moreover, muscle tissue ChE sensitivity to the organophosphate pesticide methyl-paraoxon was evaluated by determining the inhibition kinetic constants for its progressive irreversible inhibition by methyl-paraoxon as well as the 50% inhibitory concentration (IC50) for 30 min for each species. The present results indicate that acetylcholinesterase (AChE) must be present in the muscle from P. mesopotamicus, L. macrocephalus, and P. lineatus and that O. niloticus possesses an atypical cholinesterase or AChE and butyrylcholinesterase (BChE). Furthermore, there is a large difference regarding the sensitivity of these enzymes to methyl-paraoxon. The determined IC50 values for 30 min were 70 nM (O. niloticus), 258 nM (P. lineatus), 319 nM (L. macrocephalus), and 1578 nM (P. mesopotamicus). The results of the present study also indicate that the use of efficient methods for extracting these enzymes, their kinetic characterization, and determination of sensitivity differences between AChE and BChE to organophosphate compounds are essential for the determination of accurate ChE activity levels for environmental monitoring programs. © 2014 SETAC.

  11. Synthesis of novel 5-(aroylhydrazinocarbonyl)escitalopram as cholinesterase inhibitors.

    PubMed

    Nisa, Mehr-Un; Munawar, Munawar A; Iqbal, Amber; Ahmed, Asrar; Ashraf, Muhammad; Gardener, Qurra-Tul-Ann A; Khan, Misbahul A

    2017-09-29

    A novel series of 5-(aroylhydrazinocarbonyl)escitalopram (58-84) have been designed, synthesized and tested for their inhibitory potential against cholinesterases. 3-Chlorobenzoyl- (71) was found to be the most potent compound of this series having IC 50 1.80 ± 0.11 μM for acetylcholinesterase (AChE) inhibition. For the butyrylcholinesterase (BChE) inhibition, 2-bromobenzoyl- (76) was the most active compound of the series with IC 50 2.11 ± 0.31 μM. Structure-activity relationship illustrated that mild electron donating groups enhanced enzyme inhibition while electron withdrawing groups reduced the inhibition except o-NO 2 . However, size and position of the substituents affected enzyme inhibitions. . In docking study of AChE, the ligands 71, 72 and 76 showed the scores of 5874, 5756 and 5666 and ACE of -64.92,-203.25 and -140.29 kcal/mol, respectively. In case of BChE, ligands 71, 76 and 81 depicted high scores 6016, 6150 and 5994 with ACE values -170.91, -256.84 and -235.97 kcal/mol, respectively. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  12. Inhibition of cholinesterase and monoamine oxidase-B activity by Tacrine-Homoisoflavonoid hybrids.

    PubMed

    Sun, Yang; Chen, Jianwen; Chen, Xuemin; Huang, Ling; Li, Xingshu

    2013-12-01

    A series of Tacrine-Homoisoflavonoid hybrids were designed, synthesised and evaluated as inhibitors of cholinesterases (ChEs) and human monoamine oxidases (MAOs). Most of the compounds were found to be potent against both ChEs and MAO-B. Among these hybrids, compound 8b, with a 6 carbon linker between tacrine and (E)-7-hydroxy-3-(4-methoxybenzylidene)chroman-4-one, proved to be the most potent against AChE and MAO-B with IC50 values of 67.9 nM and 0.401 μM, respectively. This compound was observed to cross the blood-brain barrier (BBB) in a parallel artificial membrane permeation assay for the BBB (PAMPA-BBB). The results indicated that compound 8b is an excellent multifunctional promising compound for development of novel drugs for Alzheimer's disease (AD). Copyright © 2013 Elsevier Ltd. All rights reserved.

  13. Design and synthesis of novel 1,4-benzodiazepine derivatives and their biological evaluation as cholinesterase inhibitors.

    PubMed

    Mohamed, Lamia Wagdy; El-Yamany, Mohamed F

    2012-08-01

    A new series of 1,4-benzodiazepine-2,5-dione structurally related to cyclopenin has been synthesized. The new compounds were assayed in vivo and in vitro for their ability to inhibit acetylcholinesterase enzyme and were found to have potent reversible anticholinesterase activity when tested in vitro for isolated frog rectus abdominis and guinea pig ileum in addition to increasing brain cholinesterase level in rats when percentage inhibition were tested in vivo, moreover compounds 5a, 5b, 5c and 5g were the most active. LD(50) was performed for these derivatives and they displayed high safety margin.

  14. Characterization of cholinesterases in the damselfish Sergeant major (Abudefduf saxatilis).

    PubMed

    Rodríguez-Fuentes, Gabriela; Soto, Mélina; Luna-Ramírez, Karen

    2013-10-01

    Cholinesterase (ChE) activity has been used for many years as a biomarker of exposure to organophosphate and carbamate pesticides. Recent studies have demonstrated that there could be biological factors that determine ChE type and levels; thus, juvenile Sergeant major (Abudefduf saxatilis) ChE enzymes were biochemically characterized. ChE enzymes found in the head and trunk were evaluated for their substrate preference and sensitivity to selective inhibitors. The use of the head and trunk was chosen as a strategy to reduce dissection time and to ensure sample uniformity between stations. The results indicated that there are two types of ChE enzymes in the head: acetylcholinesterase (AChE) and atypical butyrylcholinesterase (BChE) that exhibits intermediate characteristics of human AChE and BChE activities. Atypical BChE is predominantly found in the trunk. The results also indicated that the ChE activity found in A. saxatilis may be used as a biomarker in studies monitoring the Mexican Caribbean. Copyright © 2013 Elsevier Inc. All rights reserved.

  15. Cholinesterase inhibition and behavioral toxicity of carbofuran on Oreochromis niloticus early life stages.

    PubMed

    Pessoa, P C; Luchmann, K H; Ribeiro, A B; Veras, M M; Correa, J R M B; Nogueira, A J; Bainy, A C D; Carvalho, P S M

    2011-10-01

    Nile tilapia Oreochromis niloticus at 9 days post-hatch were exposed in semi-static experiments to the carbamate insecticide carbofuran, which is applied in agricultural systems in Brazil. Although the molecular mechanism of carbofuran toxicity is well known, a detailed understanding of the ecological mechanisms through which carbofuran effects can propagate towards higher levels of biological organization in fish is incomplete. Mortality rates were quantified for larvae exposed for 96 h to 8.3, 40.6, 69.9, 140, 297 and 397 μg/L carbofuran, and the LC(50) 96 h was 214.7 μg/L. In addition, the biochemical biomarker cholinesterase inhibition and behavioral biomarkers related to vision, swimming, prey capture and predator avoidance were quantified in individual larvae, as well as their growth in weight. The behavioral parameters were quantified by analysis of digitally recorded videos of individual larvae within appropriate experimental setups. The activity of the enzyme cholinesterase decreased after exposure to carbofuran with a lowest observed effects concentration (LOEC) of 69.9 μg/L. Visual acuity deficits were detected after carbofuran exposure with a LOEC of 40.6 μg/L. Swimming speed decreased with carbofuran exposure, with a LOEC of 397.6 μg/L. The number of attacks to prey (Daphnia magna nauplii) decreased in larvae exposed to carbofuran, with a LOEC of 397.6 μg/L. Growth in weight was significantly reduced in a dose dependent manner, and all carbofuran groups exhibited a statistically significant decrease in growth when compared to controls (p<0.05). The number of predator attacks necessary to capture larvae decreased after exposure to carbofuran, and the LOEC was 69.9 μg/L. These results show that exposure of sensitive early life stages of tilapia O. niloticus to sublethal concentrations of carbofuran can affect fundamental aspects of fish larval ecology that are relevant to recruitment of fish populations, and that can be better understood by the

  16. Tritium labeling of a powerful methylphosphonate inhibitor of cholinesterase: synthesis and biological applications

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Balan, A.; Barness, I.; Simon, G.

    1988-02-15

    7-(Methylethoxy phosphinyloxy)-1-methyl-quinolinium iodide (MEPQ), a powerful anti-cholinesterase methylphosphonate ester, was labeled with tritium (9 Ci/mmol) at the methylphosphonyl moiety (TCH2P(O)(OR)X) by an iodine-tritium replacement reaction. Kinetic measurements of the rate of inhibition of acetylcholinesterase (AChE) by (/sup 3/H)MEPQ and its rate of hydrolysis in alkaline solution confirmed the identity of (/sup 3/H)MEPQ with authentic MEPQ, which was prepared by the same reaction sequences. Gel-filtration experiments verified the radiospecificity of (/sup 3/H)MEPQ. In vitro radiolabeling of both AChE and butyrylcholinesterase along with the whole-body autoradiography of (/sup 3/H)MEPQ-treated mice suggests that (/sup 3/H)MEPQ is a convenient marker for studying biological systemsmore » containing these esterases.« less

  17. Pharmacokinetics and effects on serum cholinesterase activities of organophosphorus pesticides acephate and chlorpyrifos in chimeric mice transplanted with human hepatocytes.

    PubMed

    Suemizu, Hiroshi; Sota, Shigeto; Kuronuma, Miyuki; Shimizu, Makiko; Yamazaki, Hiroshi

    2014-11-01

    Organophosphorus pesticides acephate and chlorpyrifos in foods have potential to impact human health. The aim of the current study was to investigate the pharmacokinetics of acephate and chlorpyrifos orally administered at lowest-observed-adverse-effect-level doses in chimeric mice transplanted with human hepatocytes. Absorbed acephate and its metabolite methamidophos were detected in serum from wild type mice and chimeric mice orally administered 150mg/kg. Approximately 70% inhibition of cholinesterase was evident in plasma of chimeric mice with humanized liver (which have higher serum cholinesterase activities than wild type mice) 1day after oral administrations of acephate. Adjusted animal biomonitoring equivalents from chimeric mice studies were scaled to human biomonitoring equivalents using known species allometric scaling factors and in vitro metabolic clearance data with a simple physiologically based pharmacokinetic (PBPK) model. Estimated plasma concentrations of acephate and chlorpyrifos in humans were consistent with reported concentrations. Acephate cleared similarly in humans and chimeric mice but accidental/incidental overdose levels of chlorpyrifos cleared (dependent on liver metabolism) more slowly from plasma in humans than it did in mice. The data presented here illustrate how chimeric mice transplanted with human hepatocytes in combination with a simple PBPK model can assist evaluations of toxicological potential of organophosphorus pesticides. Copyright © 2014 Elsevier Inc. All rights reserved.

  18. Acetylcholine content and cholinesterase activity as related to the combined effects of allergen and radiation. [Rats, gamma radiation

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Lipshits, R.U.; Kratinova, M.A.

    1977-01-01

    Rats were given intraperitoneal injections of antigen and exposed to 200 R of gamma radiation. Acetylcholine content and cholinesterase activity of blood were analyzed every 5 days for 30 days. The interval between sensitization and irradiation determined the direction of changes in allergic reactions. The radiation appreciably attenuated active sensitization of rats. The degree of sensitization was related to changes in cholinergic processes. The data confirmed the assumption that cholinergic systems are involved in the mechanisms of change in allergic reactivity under the influence of radiation. (HLW)

  19. Cholinesterase inhibitors in Alzheimer's disease and Lewy body spectrum disorders: the emerging pharmacogenetic story

    PubMed Central

    2009-01-01

    This review provides an update on the current state of pharmacogenetic research in the treatment of Alzheimer's disease (AD) and Lewy body disease (LBD) as it pertains to the use of cholinesterase inhibitors (ChEI). AD and LBD are first reviewed from clinical and pathophysiological perspectives. This is followed by a discussion of ChEIs used in the symptomatic treatment of these conditions, focusing on their unique and overlapping pharmacokinetic and pharmacodynamic profiles, which can be used to identify candidate genes for pharmacogenetics studies. The literature published to date is then reviewed and limitations are discussed. This is followed by a discussion of potential endophenotypes which may help to refine future pharmacogenetic studies of response and adverse effects to ChEIs. PMID:20038497

  20. Long-Term Efficacy and Toxicity of Cholinesterase Inhibitors in the Treatment of Alzheimer Disease

    PubMed Central

    Hogan, David B

    2014-01-01

    Though the symptoms of Alzheimer disease go on for years, the phase 3 trials of the cholinesterase inhibitors (ChEIs), the current mainstay of symptomatic pharmacotherapy for this condition, were typically of only 3- to 6-months’ duration. We have limited data on long-term (that is, a year or more) therapy with these agents. In this review, we explore the available information on the biological and clinical effects of long-term ChEI therapy, what happens when these agents are discontinued, and examine what others have recommended. An individualized approach to deciding on whether to carry on with a ChEI should be taken. If continued, treatment goals should be clarified and patients monitored over time, for both drug-related benefits and adverse effects. PMID:25702360

  1. Mechanism of action of ionizing radiation on hexokinase and cholinesterase activity in the rat brain, in the presence of altered function of M-cholinergic structures. [X radiation

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Khripchenko, I.P.; Kukulyanskaya, M.F.; Markina, V.L.

    1977-01-01

    Data are submitted on activity of hexokinase and isozymes thereof, and cholinesterase in subcellular fractions of the brain in the case of inhibition and stimulation of M-cholinoreactive structures under the influence of a relatively small dose, 40 R, of ionizing radiation.

  2. Proline-Based Carbamates as Cholinesterase Inhibitors.

    PubMed

    Pizova, Hana; Havelkova, Marketa; Stepankova, Sarka; Bak, Andrzej; Kauerova, Tereza; Kozik, Violetta; Oravec, Michal; Imramovsky, Ales; Kollar, Peter; Bobal, Pavel; Jampilek, Josef

    2017-11-14

    Series of twenty-five benzyl (2S)-2-(arylcarbamoyl)pyrrolidine-1-carboxylates was prepared and completely characterized. All the compounds were tested for their in vitro ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), and the selectivity of compounds to individual cholinesterases was determined. Screening of the cytotoxicity of all the compounds was performed using a human monocytic leukaemia THP-1 cell line, and the compounds demonstrated insignificant toxicity. All the compounds showed rather moderate inhibitory effect against AChE; benzyl (2 S )-2-[(2-chlorophenyl)carbamoyl]pyrrolidine-1-carboxylate (IC 50 = 46.35 μM) was the most potent agent. On the other hand, benzyl (2 S )-2-[(4-bromophenyl)-] and benzyl (2 S )-2-[(2-bromophenyl)carbamoyl]pyrrolidine-1-carboxylates expressed anti-BChE activity (IC 50 = 28.21 and 27.38 μM, respectively) comparable with that of rivastigmine. The ortho -brominated compound as well as benzyl (2 S )-2-[(2-hydroxyphenyl)carbamoyl]pyrrolidine-1-carboxylate demonstrated greater selectivity to BChE. The in silico characterization of the structure-inhibitory potency for the set of proline-based carbamates considering electronic, steric and lipophilic properties was provided using comparative molecular surface analysis (CoMSA) and principal component analysis (PCA). Moreover, the systematic space inspection with splitting data into the training/test subset was performed to monitor the statistical estimators performance in the effort to map the probability-guided pharmacophore pattern. The comprehensive screening of the AChE/BChE profile revealed potentially relevant structural and physicochemical features that might be essential for mapping of the carbamates inhibition efficiency indicating qualitative variations exerted on the reaction site by the substituent in the 3'-/4'-position of the phenyl ring. In addition, the investigation was completed by a molecular docking study of recombinant human AChE.

  3. Development of square wave voltammetry method for the assessment of organophosphorus compound impact on the cholinesterase of Pheretima with 2,6-dichloroindophenol as a redox indicator.

    PubMed

    Qiu, Jingxia; Chen, Jin; Ma, Qianqian; Miao, Yuqing

    2009-09-01

    A square wave voltammetry method was developed for the assessment of organophosphorus (OPs) compound impact on the cholinesterase of Pheretima with 2,6-dichloroindophenol (2,6-DCIP) as a redox indicator. The substrate of acetylthiocholine is hydrolysed by the cholinesterase (ChE) from soil animal pheretima, and the produced thiocholine reacts with the 2,6-DCIP to give obvious shift of electrochemical signal. The inhibition of ChE was assessed by measuring the enzyme activity before and after incubating with parathion-methyl. The reduction peak current of 2,6-DCIP decreases with the time of enzymatical reaction. The ChE loses almost 32.74% activity after 10 min incubation with 1ng mL(-1) paraoxon and 54.62% with 10 microg mL(-1) paraoxon, while the activity that corresponds to 100 microg mL(-1) paraoxon was nearly completely inhibited. This method can be employed to assess the inhibition of ChE and investigate OPs impact on environmental animals.

  4. In Vivo Reactivation by Oximes of Inhibited Blood, Brain and Peripheral Tissue Cholinesterase Activity Following Exposure to Nerve Agents in Guinea Pigs

    DTIC Science & Technology

    2010-01-01

    L.W.Harris, D.L. Stitcher , Reactivation of VX-inhibited cholinesterase by 2-PAM and HS-6 in rats, Drug Chem. Toxicol. 6 (1983) 235–240. [9] P.M. Lundy, T.-M...rat, monkey and human, Arch. Toxicol. 68 (1994) 648–655. 2 gical In [ [ 14 T.-M. Shih et al. / Chemico-Biolo27] L.W. Harris, W.C. Heyl, D.L. Stitcher

  5. TESTING FOR DEPARTURES FROM ADDITIVITY FOR A 2:1 MIXTURE OF CHLORPYRIFOS AND CARBARYL ON CHOLINESTERASE ACTIVITY IN BRAIN, PLASMA, AND RED BLOOD CELLS OF LONG EVANS RATS.

    EPA Science Inventory

    Detecting and characterizing interactions among chemicals is an important environmental issue. This study was conducted to test for the existence of a significant departure from additivity for a mixture of two cholinesterase (ChE)-inhibiting pesticides: chlorpyrifos (CPF), an org...

  6. Novel cucurbitane triterpenoids and anti-cholinesterase activities of constituents from Momordica charantia L.

    PubMed

    Kuanhuta, Wichut; Aree, Thammarat; Pornpakakul, Surachai; Sawasdee, Pattara

    2014-06-01

    The C-19 epimers of 5beta,19-epoxycucurbita-6,23(E),25(26)-triene-3f,19-diol (1) and 5/,19-epoxy-25-methoxycucurbita-6,23-diene-3beta,19-diol (2) along with (19R,23E)-5beta,19-epoxy-19-methoxycucurbita-6,23,25-trien-3beta-ol (3), (23E)-5beta,19-epoxycucurbita-6,23-diene-3beta,25-diol (4), ligballinol (5), charantin (6) and momordicoside K(7) were isolated from the green fruits of Momordica charantia. The (S)-epimers of 1 and 2 are the first reports in nature. The acetyl- and butyryl-cholinesterase inhibitory activities of the isolated compounds were evaluated, and 5 showed the highest activity of these compounds against butyrylcholinesterase (IC50 = 32.20 microM) with a reversible and non-competitive inhibition mode.

  7. Measurement of K-27, an oxime-type cholinesterase reactivator by high-performance liquid chromatography with electrochemical detection from different biological samples.

    PubMed

    Gyenge, Melinda; Kalász, Huba; Petroianu, George A; Laufer, Rudolf; Kuca, Kamil; Tekes, Kornélia

    2007-08-17

    K-27 is a bisquaternary asymmetric pyridinium aldoxime-type cholinesterase reactivator of use in the treatment of poisoning with organophosphorous esterase inhibitors. A sensitive, simple and reliable reverse-phase high-performance liquid chromatographic method with electrochemical detection was developed for the measurement of K-27 concentrations in rat brain, cerebrospinal fluid, serum and urine samples. Male Wistar rats were treated intramuscularly with K-27 and the samples were collected 60 min later. Separation was carried out on an octadecyl silica stationary phase and a disodium phosphate solution (pH 3.7) containing citric acid, octane sulphonic acid and acetonitrile served as mobile phase. Measurements were carried out at 30 degrees C at E(ox) 0.65 V. The calibration curve was linear through the range of 10-250 ng/mL. Accuracy, precision and the limit of detection calculated were satisfactory according to internationally accepted criteria. Limit of quantitation was 10 ng/mL. The method developed is reliable and sensitive enough for monitoring K-27 levels from different biological samples including as little as 10 microL of cerebrospinal fluid. The method--with slight modification in the composition of the mobile phase--can be used to measure a wide range of other related pyridinium aldoxime-type cholinesterase reactivators.

  8. Recovery of cholinesterase activity in mallard ducklings administered organophosphorus pesticides

    USGS Publications Warehouse

    Fleming, W.J.; Bradbury, S.P.

    1981-01-01

    Oral doses of the organophosphorus pesticides acephate, dicrotophos, fensulfothion, fonofos, malathion, and parathion were administered to mallard ducklings (Anas platyrhynchos), and brain and plasma cholinesterase (ChE) activities were determined for up to 77 d after dosing. In vivo recovery of brain ChE activity to within 2 standard deviations of the mean activity of undosed birds occurred within 8 d, after being depressed an average of 25-58% at 24 h after dosing. In vivo recovery of plasma ChE appeared as fast as or faster than that of brain, but the pattern of recovery was more erratic and therefore statistical comparison with brain ChE recovery was not attempted. In vitro tests indicated that the potential for dephosphorylation to contribute to in vivo recovery of inhibited brain ChE differed among chemical treatments. Some ducklings died as a result of organophosphate dosing. In an experiment in which ducklings within each treatment group received the same dose (mg/kg), the brain ChE activity in birds that died was less than that in birds that survived. Brain ChE activities in ducklings that died were significantly different among pesticide treatments: fensulfothion > parathion> acephate > malathion (p < 0.05).

  9. Simulating cholinesterase inhibition in birds caused by dietary insecticide exposure

    USGS Publications Warehouse

    Corson, M.S.; Mora, M.A.; Grant, W.E.

    1998-01-01

    We describe a stochastic simulation model that simulates avian foraging in an agricultural landscape to evaluate factors affecting dietary insecticide exposure and to predict post-exposure cholinesterase (ChE) inhibition. To evaluate the model, we simulated published field studies and found that model predictions of insecticide decay and ChE inhibition reasonably approximated most observed results. Sensitivity analysis suggested that foraging location usually influenced ChE inhibition more than diet preferences or daily intake rate. Although organophosphorus insecticides usually caused greater inhibition than carbamate insecticides, insecticide toxicity appeared only moderately important. When we simulated impact of heavy insecticide applications during breeding seasons of 15 wild bird species, mean maximum ChE inhibition in most species exceeded 20% at some point. At this level of inhibition, birds may experience nausea and/or may exhibit minor behavioral changes. Simulated risk peaked in April–May and August–September and was lowest in July. ChE inhibition increased with proportion of vegetation in the diet. This model, and ones like it, may help predict insecticide exposure of and sublethal ChE inhibition in grassland animals, thereby reducing dependence of ecological risk assessments on field studies alone.

  10. Effects of carbamates on whole blood cholinesterase activity: chemical protection against soman.

    PubMed

    Heyl, W C; Harris, L W; Stitcher, D L

    1980-01-01

    The toxicity (LD50) of several carbamates, all reversible inhibitors of cholinesterase (ChE), were determined in male rabbits. These include isopropyl methylphenyl carbamate (IMPC), pyridostigmine, neostigmine, benzpyrinium and physostigmine. When 1/9 of the LD50 of the above carbamates was individually combined with atropine (A) and benactyzine (B), mecamylamine (M) or chloropromazine (CPZ) and administered to rabbits in a pretreatment regimen, most animals could be protected from a 10 LD50 challenge of Soman. If CPZ, M or B was omitted from this regimen, no rabbits survived this challenge of Soman. The protection afforded against Soman was found to be related to reversible inhibition of ChE by the carbamates; reversible ChE inhibition varied with the route of injection and with the physical properties of the carbamate. Oral administration of pyridostigmine, a quaternary carbamate, provided protection for 24 hours. When the pretreatment included four components (pyridostigmine, A, M and B), the LD50 of Soman was raised 30.8 times in rabbits.

  11. Insights into cholinesterase inhibitory and antioxidant activities of five Juniperus species.

    PubMed

    Orhan, Nilufer; Orhan, Ilkay Erdogan; Ergun, Fatma

    2011-09-01

    In vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory and antioxidant activities of the aqueous and ethanol extracts of the leaves, ripe fruits, and unripe fruits of Juniperus communis ssp. nana, Juniperus oxycedrus ssp. oxycedrus, Juniperus sabina, Juniperus foetidissima, and Juniperus excelsa were investigated in the present study. Cholinesterase inhibition of the extracts was screened using ELISA microplate reader. Antioxidant activity of the extracts was tested by 2,2-diphenyl-1-picrylhydrazyl (DPPH) and superoxide radical scavenging, ferrous ion-chelating, and ferric-reducing antioxidant power (FRAP) assays. Total phenol and flavonoid contents of the extracts were determined spectrophotometrically. The extracts had low or no inhibition towards AChE, whereas the leaf aqueous extract of J. foetidissima showed the highest BChE inhibition (93.94 ± 0.01%). The leaf extracts usually exerted higher antioxidant activity. We herein describe the first study on anticholinesterase and antioxidant activity by the methods of ferrous ion-chelating, superoxide radical scavenging, and ferric-reducing antioxidant power (FRAP) assays of the mentioned Juniperus species. Copyright © 2011 Elsevier Ltd. All rights reserved.

  12. The Arabidopsis thaliana ortholog of a purported maize cholinesterase gene encodes a GDSL-lipase

    PubMed Central

    Muralidharan, Mrinalini; Buss, Kristina; Larrimore, Katherine E.; Segerson, Nicholas A.; Kannan, Latha

    2013-01-01

    Acetylcholinesterase is an enzyme that is intimately associated with regulation of synaptic transmission in the cholinergic nervous system and in neuromuscular junctions of animals. However the presence of cholinesterase activity has been described also in non-metazoan organisms such as slime molds, fungi and plants. More recently, a gene purportedly encoding for acetylcholinesterase was cloned from maize. We have cloned the Arabidopsis thaliana homolog of the Zea mays gene, At3g26430, and studied its biochemical properties. Our results indicate that the protein encoded by the gene exhibited lipase activity with preference to long chain substrates but did not hydrolyze choline esters. The At3g26430 protein belongs to the SGNH clan of serine hydrolases, and more specifically to the GDS(L) lipase family. PMID:23430565

  13. COPD Exacerbation and Cholinesterase Therapy in Dementia Patients.

    PubMed

    Mahan, Rebecca J; Blaszczyk, Amie Taggart

    2016-04-01

    Chronic obstructive pulmonary disease (COPD) is a nonreversible inflammatory condition of the lungs. Acetylcholine is a neurotransmitter involved in autonomic regulation of the airways, resulting in bronchoconstriction and mucous production. Cholinesterase inhibitors (ChEIs), a cornerstone therapy of dementia treatment, increase acetylcholine. Theoretically, ChEI use in patients with COPD can place patients at increased risk of exacerbation secondary to increased acetylcholine activity. A retrospective chart review was performed comparing veterans with dementia and COPD who received ChEIs with those who did not at the Veterans Affairs North Texas Health Care System. Frequency of exacerbation in the first 90 days following ChEI initiation was compared. Secondary outcomes assessed exacerbation severity and a potential protective effect of inhaled anticholinergics. A total of 94 patients were eligible for the study; 52 received a ChEI and 42 did not. The risk of exacerbation over 90 days was higher in the ChEI users with 10 (19%) experiencing an exacerbation compared with 3 (7%) in the nonusers (P = 0.133), showing a clinically significant trend. Of the patients experiencing an exacerbation, 2 patients on ChEIs had multiple exacerbations over the 90 days. The use of inhaled anticholinergics was not found to decrease the risk of exacerbation. The use of ChEIs may increase the risk of COPD exacerbation in the first 90 days of therapy in patients with dementia and COPD. This finding is clinically significant as previous studies have indicated no risk.

  14. Pharmacokinetic and pharmacodynamic properties of cholinesterase inhibitors donepezil, tacrine, and galantamine in aged and young Lister hooded rats.

    PubMed

    Goh, Catherine W; Aw, Chiu Cheong; Lee, Jasinda H; Chen, Christopher P; Browne, Edward R

    2011-03-01

    Physiological alterations that may change pharmacological response accompany aging. Pharmacokinetic/pharmacodynamic properties of cholinesterase inhibitors (ChEIs) used in the treatment of Alzheimer's disease, donepezil, tacrine, and galantamine, were investigated in an aged Lister hooded rat model. Intravenous and oral 6-h blood sampling profiles in old (30 months old) and young (7 months old) rats revealed pharmacokinetic changes similar to those in humans with an approximately 40% increase in C(max) of galantamine and prolonged t(1/2) (1.4-fold) and mean residence time (1.5-fold) of donepezil. Tacrine disposition was maintained with age, and area under the concentration-time curve and clearance in old rats were similar to those in young rats for all drugs tested as was bioavailability. Old rats showed a trend of increased pharmacodynamic sensitivity (<20%) to ChEIs in cholinesterase activity assays, which was attributed to pharmacokinetic effects because a trend of higher blood and brain concentrations was seen in the old rats although brain/blood ratios remained unaffected. Enhanced cholinergic-mediated behaviors such as tremor, hypothermia, salivation, and lacrimation were also observed in the old rats, which could not be accounted for by a similar magnitude of change in pharmacokinetics. A decrease in expression of muscarinic acetylcholine receptor subtype 2 detected in old rat brains was postulated to play a role. Greater age effects in both pharmacokinetics and pharmacodynamics of donepezil and tacrine were seen in previous studies with Fischer 344 rats, indicating a potential risk in overreliance on this rat strain for aging studies.

  15. Effects of pyridostigmine and cholinolytics on cholinesterase and acetylcholine in Soman poisoned rats.

    PubMed

    Stitcher, D L; Harris, L W; Heyl, W C; Alter, S C

    1978-01-01

    Soman reduced blood and brain cholinesterase (ChE) activity to less than 15% and increased cerebral acetylcholine (ACh) levels to 137.4% of control. When pyridostigmine (P) was used as a prophylactic adjunct, it reduced blood ChE activity to 31.6% of control, failed to significantly alter brain ChE activity, and protected more than 70% of the blood (but not brain enzyme) from phosphonylation by soman. Benactyzine (B) was more effective than atropine (A) in reducing cerebral ACh concentrations, while a combination of the two was more effective than either alone. A prophylaxis of P + A + B was effective in controlling ACh levels in rats poisoned with one LD50 dose of Soman. Since P did not diminish the effects of the cholinolytics on cerebral ACh, this (together with the enzyme data) suggests that the two cholinolytics alone provided the central protection.

  16. Divergent effects of postmortem ambient temperature on organophosphorus- and carbamate-inhibited brain cholinesterase activity in birds

    USGS Publications Warehouse

    Hill, E.F.

    1989-01-01

    Time- and temperature-dependent postmortem changes in inhibited brain cholinesterase (ChE) activity may confound diagnosis of field poisoning of wildlife by anticholinesterase pesticide. Carbamate-inhibited ChE activity may return to normal within 1 to 2 days of exposure of intact carcass to moderate ambient temperature (18-32C). Organophosphorus-inhibited ChE activity becomes more depressed over the same time. Uninhibited ChE activity was resilient to above freezing temperature to 32C for 1 day and 25C for 3 days. Carbamate- and organophosphorus-inhibited ChE can be separated by incubation of homogenate for 1 hour at physiological temperatures; carbamylated ChE can be readily reactivated while phosphorylated ChE cannot.

  17. Furoquinoline Alkaloids from the Leaves of Evodia lepta as Potential Cholinesterase Inhibitors and their Molecular Docking.

    PubMed

    Sichaem, Jirapast; Rojpitikul, Thanawan; Sawasdee, Pattara; Lugsannangarm, Kiattisak; Santi, Tip-pyang

    2015-08-01

    Nine furoquinoline alkaloids (1-9) were isolated from the leaves of Evodia lepta based on bioassay-guided fractionation and chromatographic techniques. All isolates were evaluated for their cholinesterase (ChEs) inhibitory activities, in which kokusaginine (7) and melineurine (5) exhibited the highest activity toward AChE and BChE, respectively. Lineweaver-Burk plots indicated that 5 and 7 were mixed mode inhibitors of both ChE enzymes. Molecular docking studies on the binding sites of AChE and BChE were performed in order to afford a molecular insight into the mode of action of these active compounds. From this study these compounds have emerged as promising molecules for Alzheimer's disease therapy.

  18. Accumulation of phenolic compounds in in vitro cultures and wild plants of Lavandula viridis L'Hér and their antioxidant and anti-cholinesterase potential.

    PubMed

    Costa, Patrícia; Gonçalves, Sandra; Valentão, Patrícia; Andrade, Paula B; Romano, Anabela

    2013-07-01

    In this study, we evaluated the phenolic profile, antioxidant and anti-cholinesterase potential of different extracts from wild plants and in vitro cultures of Lavandula viridis L'Hér. The HPLC-DAD analysis allowed the identification and quantification of 3-O-caffeoylquinic, 4-O-caffeoylquinic, 5-O-caffeoylquinic and rosmarinic acids, and luteolin and pinocembrin. Water/ethanol extract from in vitro cultures contained the highest amount of the identified phenolic compounds (51652.92 mg/kg). To investigate the antioxidant activity we used Trolox equivalent antioxidant capacity, oxygen radical absorbance capacity, Fe(2+) chelation activity and the inhibition of Fe(2+)-induced lipid peroxidation in mouse brain homogenates (in vitro). Overall, all the extracts from both wild plants and in vitro cultures exhibited ability to scavenge free radicals, to chelate Fe(2+) and to protect against lipid peroxidation. In addition, the extracts from L. viridis were active in inhibiting both acetylcholinesterase and butyrylcholinesterase (Ellman's method). Our findings suggest that L. viridis in vitro cultures represent a promising alternative for the production of active metabolites with antioxidant and anti-cholinesterase activity. Copyright © 2013 Elsevier Ltd. All rights reserved.

  19. Characterizations of cholinesterases in golden apple snail (Pomacea canaliculata).

    PubMed

    Zou, Xiang-Hui; Xie, Heidi Qun-Hui; Zha, Guang-Cai; Chen, Vicky Ping; Sun, Yan-Jie; Zheng, Yu-Zhong; Tsim, Karl Wah-Keung; Dong, Tina Ting-Xia; Choi, Roy Chi-Yan; Luk, Wilson Kin-Wai

    2014-07-01

    Cholinesterases (ChEs) have been identified in vertebrates and invertebrates. Inhibition of ChE activity in invertebrates, such as bivalve molluscs, has been used to evaluate the exposure of organophosphates, carbamate pesticides, and heavy metals in the marine system. The golden apple snail (Pomacea canaliculata) is considered as one of the worst invasive alien species harmful to rice and other crops. The ChE(s) in this animal, which has been found recently, but poorly characterized thus far, could serve as biomarker(s) for environmental surveillance as well as a potential target for the pest control. In this study, the tissue distribution, substrate preference, sensitivity to ChE inhibitors, and molecular species of ChEs in P. canaliculata were investigated. It was found that the activities of both AChE and BChE were present in all test tissues. The intestine had the most abundant ChE activities. Both enzymes had fair activities in the head, kidney, and gills. The BChE activity was more sensitive to tetra-isopropylpyrophosphoramide (iso-OMPA) than the AChE. Only one BChE molecular species, 5.8S, was found in the intestine and head, whereas two AChE species, 5.8S and 11.6S, were found there. We propose that intestine ChEs of this snail may be potential biomarkers for manipulating pollutions.

  20. Brain cholinesterase activity of nestling great egrets, snowy egrets, and black-crowned night-herons

    USGS Publications Warehouse

    Custer, T.W.; Ohlendorf, H.M.

    1989-01-01

    Inhibition of brain cholinesterase (ChE) activity in birds is often used to diagnose exposure or death from organophosphorus or carbmate pesticides. Brain ChE activity in the young of altricial species increase with age; however, this relationship has only been demonstrated in the European starling (Sturnus vulgaris). Brain ChE activity of nestling great egrets (Casmerodius albus) collected from a colony in Texas increased significantly with age and did not differ among individuals from different nests. Brain ChE activity of nestling snowy egrets (Egretta thula) and black-crowned night -herons (Nycticorax nycticorax) collected in one colony each from Rhode Island, Texas, and California also increased significantly with age and did not differ among individuals from different nests or colonies. This study further demonstrates that age must be considered when evaluating exposure of nestling altricial birds to ChE inhibitors.

  1. Brain cholinesterase activity of nestling great egrets snowy egrets and black-crowned night-herons

    USGS Publications Warehouse

    Custer, T.W.; Ohlendorf, H.M.

    1989-01-01

    Inhibition of brain cholinesterase (ChE) activity in birds is often used to diagnose exposure or death from organophosphorus or carbamate pesticides. Brain ChE activity in the young of altricial species increases with age; however, this relationship has only been demonstrated in the European starling (Sturnus vulgaris). Brain ChE activity of nestling great egrets (Casmerodius albus) collected from a colony in Texas (USA) increased significantly with age and did not differ among individuals from different nests. Brain ChE activity of nestling snowy egrets (Egretta thula) and black-crowned night-herons (Nycticorax nycticorax) collected in one colony each from Rhode Island, Texas and California (USA) also increased significantly with age and did not differ among individuals from different nests or colonies. This study further demonstrates that age must be considered when evaluating exposure of nestling altricial birds to ChE inhibitors.

  2. Cholinesterase inhibitor soman increases inositol trisphosphate in rat brain. (Reannouncement with new availability information)

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Mobley, P.L.

    1990-12-31

    Studies were conducted to determine the effect of the cholinesterase inhibitor soman on the amount of inositol trisphosphate in the neocortex, striatum, cerebellum, and medulla-pons regions of rat brain in vivo. The studies indicate that treatment with soman increase inositol trisphosphate in the neocortex and striatum, but not in the cerebellum or medulla-pons region. In the neocortex the most pronounced increases were observed in animals with severe poisoning symptoms; however, inositol trisphophate was also found to be elevated in animals with only mild poisoning symptoms. A variety of evidence suggests that the receptor-mediated hydrolysis of phosphatidyl inositol results in themore » formation of inositol trisphosphate (IP3) and diacylglycerol, both of which function as intracellular signal messengers, and that this mechanism represents a major signal transduction system through which extracellular signals can influence intracellular events.« less

  3. PON1 status does not influence cholinesterase activity in Egyptian agricultural workers exposed to chlorpyrifos

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Ellison, Corie A., E-mail: cellison@buffalo.edu; Crane, Alice L., E-mail: alcrane@buffalo.edu; Bonner, Matthew R., E-mail: mrbonner@buffalo.edu

    Animal studies have shown that paraoxonase 1 (PON1) genotype can influence susceptibility to the organophosphorus pesticide chlorpyrifos (CPF). However, Monte Carlo analysis suggests that PON1 genotype may not affect CPF-related toxicity at low exposure conditions in humans. The current study sought to determine the influence of PON1 genotype on the activity of blood cholinesterase as well as the effect of CPF exposure on serum PON1 in workers occupationally exposed to CPF. Saliva, blood and urine were collected from agricultural workers (n = 120) from Egypt's Menoufia Governorate to determine PON1 genotype, blood cholinesterase activity, serum PON1 activity towards chlorpyrifos-oxon (CPOase)more » and paraoxon (POase), and urinary levels of the CPF metabolite 3,5,6-trichloro-2-pyridinol (TCPy). The PON1 55 (P ≤ 0.05) but not the PON1 192 genotype had a significant effect on CPOase activity. However, both the PON1 55 (P ≤ 0.05) and PON1 192 (P ≤ 0.001) genotypes had a significant effect on POase activity. Workers had significantly inhibited AChE and BuChE after CPF application; however, neither CPOase activity nor POase activity was associated with ChE depression when adjusted for CPF exposure (as determined by urinary TCPy levels) and stratified by PON1 genotype. CPOase and POase activity were also generally unaffected by CPF exposure although there were alterations in activity within specific genotype groups. Together, these results suggest that workers retained the capacity to detoxify chlorpyrifos-oxon under the exposure conditions experienced by this study population regardless of PON1 genotype and activity and that effects of CPF exposure on PON1 activity are minimal. -- Highlights: ► CPF exposure resulted in an increase in TCPy and decreases in BuChE and AChE. ► CPOase activity decreased in subjects with the PON1 55LM and PON1 55 MM genotypes. ► Neither PON1 genotype nor CPOase activity had an effect on BuChE or AChE inhibition.« less

  4. Cholinesterase structure: Identification of residues and domains affecting organophosphate inhibition and catalysis. Annual report, 6 March 1995-5 March 1996

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Taylor, P.W.

    1996-04-01

    In the initial year of the grant, we have made excellent progress in several arenas: (1) A crystal structure of a mouse acetylcholinesterase-fasciculin 2 complex has been solved. (2) Studies with enantiomeric organophosphates have yielded vital information on their binding orientation in the ground and transition states. (3) Studies in oxime reactivation of inhibited cholinesterase have uncovered the basis for enhanced reactivity of HI-6 compared to 2-PAM. (4) The interactions of fasciculin 2 with acetylcholinesterase have been studied by kinetic and site-specific mutagenesis methods.

  5. Planarian cholinesterase: in vitro characterization of an evolutionarily ancient enzyme to study organophosphorus pesticide toxicity and reactivation.

    PubMed

    Hagstrom, Danielle; Hirokawa, Hideto; Zhang, Limin; Radic, Zoran; Taylor, Palmer; Collins, Eva-Maria S

    2017-08-01

    The freshwater planarian Dugesia japonica has recently emerged as an animal model for developmental neurotoxicology and found to be sensitive to organophosphorus (OP) pesticides. While previous activity staining of D. japonica, which possess a discrete cholinergic nervous system, has shown acylthiocholine catalysis, it is unknown whether this is accomplished through an acetylcholinesterase (AChE), butyrylcholinesterase (BChE), or a hybrid esterase and how OP exposure affects esterase activity. Here, we show that the majority of D. japonica cholinesterase (DjChE) activity departs from conventional AChE and BChE classifications. Inhibition by classic protonable amine and quaternary reversible inhibitors (ethopropazine, donepezil, tacrine, edrophonium, BW284c51, propidium) shows that DjChE is far less sensitive to these inhibitors than human AChE, suggesting discrete differences in active center and peripheral site recognition and structures. Additionally, we find that different OPs (chlorpyrifos oxon, paraoxon, dichlorvos, diazinon oxon, malaoxon) and carbamylating agents (carbaryl, neostigmine, physostigmine, pyridostigmine) differentially inhibit DjChE activity in vitro. DjChE was most sensitive to diazinon oxon and neostigmine and least sensitive to malaoxon and carbaryl. Diazinon oxon-inhibited DjChE could be reactivated by the quaternary oxime, pralidoxime (2-PAM), and the zwitterionic oxime, RS194B, with RS194B being significantly more potent. Sodium fluoride (NaF) reactivates OP-DjChE faster than 2-PAM. As one of the most ancient true cholinesterases, DjChE provides insight into the evolution of a hybrid enzyme before the separation into distinct AChE and BChE enzymes found in higher vertebrates. The sensitivity of DjChE to OPs and capacity for reactivation validate the use of planarians for OP toxicology studies.

  6. Characterization of plasma cholinesterase from the White stork (Ciconia ciconia) and its in vitro inhibition by anticholinesterase pesticides.

    PubMed

    Oropesa, Ana-Lourdes; Gravato, Carlos; Sánchez, Susana; Soler, Francisco

    2013-11-01

    Blood plasma cholinesterase (ChE) activity is a sensitive biomarker of exposure to organophosphorus (OP) and carbamate (CB) insecticides in vertebrates. Several studies indicate that more than one ChE form may be present in blood of birds. In this study the predominant ChE activity (acetylcholinesterase - AChE- or butyrylcholinesterase - BChE-), the range of ChE activity as well as ChE age-dependent changes in non-exposed individuals of White stork (Ciconia ciconia) have been established. The in vitro sensitivity of ChE to OP and CB insecticides such as paraoxon-methyl, carbofuran and carbaryl was also investigated. Plasma ChE was characterised using three substrates (acetylthiocholine iodide, propionylthiocholine iodide, and S-butyrylthiocholine iodide) and three ChE inhibitors (eserine sulphate, BW284C51 and iso-OMPA). The results indicated that propionylthiocholine was the preferred substrate by plasma cholinesterase followed by acetylcholine and butyrylcholine and the predominant enzymatic activity in plasma of White storks was BChE. Normal plasma BChE activity in White stork was 0.32±0.01μmol/min/ml for adults and 0.28±0.03μmol/min/ml for juveniles. So, the age had no significant effect on the range of BChE activity. The study on the in vitro inhibitory potential of tested anticholinesterase pesticides on plasma ChE activity revealed that paraoxon-methyl is the most potent inhibitor followed by carbofuran and finally by carbaryl. The percentage of in vitro plasma ChE inhibition was observed to be similar between adults and juveniles. Copyright © 2013 Elsevier Inc. All rights reserved.

  7. The relationship between total cholinesterase activity and mortality in four butterfly species

    USGS Publications Warehouse

    Bargar, Timothy A.

    2012-01-01

    The relationship between total cholinesterase activity (TChE) and mortality in four butterfly species (great southern white [Ascia monuste], common buckeye [Junonia coenia], painted lady [Vanessa cardui], and julia butterflies [Dryas julia]) was investigated. Acute contact toxicity studies were conducted to evaluate the response (median lethal dose [LD50] and TChE) of the four species following exposure to the organophosphate insecticide naled. The LD50 for these butterflies ranged from 2.3 to 7.6 μg/g. The average level of TChE inhibition associated with significant mortality ranged from 26 to 67%, depending on the species. The lower bounds of normal TChE activity (2 standard deviations less than the average TChE for reference butterflies) ranged from 8.4 to 12.3 μM/min/g. As a percentage of the average reference TChE activity for the respective species, the lower bounds were similar to the inhibition levels associated with significant mortality, indicating there was little difference between the dose resulting in significant TChE inhibition and that resulting in mortality.

  8. [Comparative analysis of sensitivity of proteases (chymotrypsin and trypsin) and cholinesterases of different origin to some organophosphorus inhibitors].

    PubMed

    Rozengart, E V

    2009-01-01

    The antichymotrypsin, antitrypsin, and anticholinesterase efficiencies of four homologous series of organophosphorus inhibitors are compared: O-ethyl-S-(n-alkyl)methylthiophosphonates, O-(n-alkyl)-S-(n-butyl)methylthiophosphonates, O-(n-alkyl)-S-beta-(ethylmercaptoethylene)methylthiophosphonates, and their methylsulfomethylates. As sources of a-chymotrypsin and trypsin, commercial compounds of Worthington Biochemical Corporation and Leningrad Myasokombinat were tested. Bimolecular constant of the reaction rate was used as the measure of antienzyme efficiency. In all cases, the antichymotrypsin efficiency was lower, while the antitrypsin--essentially higher than the anticholinesterase activity of the studied inhibitors. These differences were found to much depend both on the inhibitor structure and on nature of the cholinesterase compounds.

  9. Cholinesterase inhibitors affect brain potentials in amnestic mild cognitive impairment

    PubMed Central

    Irimajiri, Rie; Michalewski, Henry J; Golob, Edward J; Starr, Arnold

    2007-01-01

    Amnestic mild cognitive impairment (MCI) is an isolated episodic memory disorder that has a high likelihood of progressing to Alzheimer’s disease. Auditory sensory cortical responses (P50, N100) have been shown to be increased in amplitude in MCI compared to older controls. We tested whether (1) cortical potentials to other sensory modalities (somatosensory and visual) were also affected in MCI and (2) cholinesterase inhibitors (ChEIs), one of the therapies used in this disorder, modulated sensory cortical potentials in MCI. Somatosensory cortical potentials to median nerve stimulation and visual cortical potentials to reversing checkerboard stimulation were recorded from 15 older controls and 15 amnestic MCI subjects (single domain). Results were analyzed as a function of diagnosis (Control, MCI) and ChEIs treatment (Treated MCI, Untreated MCI). Somatosensory and visual potentials did not differ significantly in amplitude in MCI subjects compared to controls. When ChEIs use was considered, somatosensory potentials (N20, P50) but not visual potentials (N70, P100, N150) were of larger amplitude in untreated MCI subjects compared to treated MCI subjects. Three individual MCI subjects showed increased N20 amplitude while off ChEIs compared to while on ChEIs. An enhancement of N20 somatosensory cortical activity occurs in amnestic single domain MCI and is sensitive to modulation by ChEIs. PMID:17320833

  10. Purification and studies on characteristics of cholinesterases from Daphnia magna *

    PubMed Central

    Yang, Yan-xia; Niu, Li-zhi; Li, Shao-nan

    2013-01-01

    Due to their significant value in both economy and ecology, Daphnia had long been employed to investigate in vivo response of cholinesterase (ChE) in anticholinesterase exposures, whereas the type constitution and property of the enzyme remained unclear. A type of ChE was purified from Daphnia magna using a three-step procedure, i.e., Triton X-100 extraction, ammonium sulfate precipitation, and diethylaminoethyl (DEAE)-Sepharose™-Fast-Flow chromatography. According to sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), molecular mass of the purified ChE was estimated to be 84 kDa. Based on substrate studies, the purified enzyme preferred butyrylthiocholine iodide (BTCh) [with maximum velocity (V max)/Michaelis constant (K m)=8.428 L/(min·mg protein)] to acetylthiocholine iodide (ATCh) [with V max/K m=5.346 L/(min·mg protein)] as its substrate. Activity of the purified enzyme was suppressed by high concentrations of either ATCh or BTCh. Inhibitor studies showed that the purified enzyme was more sensitive towards inhibition by tetraisopropylpyrophosphoramide (iso-OMPA) than by 1,5-bis(4-allyldimethylammoniumphenyl) pentan-3-one dibromide (BW284C51). Result of the study suggested that the purified ChE was more like a type of pseudocholinesterase, and it also suggested that Daphnia magna contained multiple types of ChE in their bodies. PMID:23549850

  11. Ferulic acid-carbazole hybrid compounds: Combination of cholinesterase inhibition, antioxidant and neuroprotection as multifunctional anti-Alzheimer agents.

    PubMed

    Fang, Lei; Chen, Mohao; Liu, Zhikun; Fang, Xubin; Gou, Shaohua; Chen, Li

    2016-02-15

    In order to search for novel multifunctional anti-Alzheimer agents, a series of ferulic acid-carbazole hybrid compounds were designed and synthesized. Ellman's assay revealed that the hybrid compounds showed moderate to potent inhibitory activity against the cholinesterases. Particularly, the AChE inhibition potency of compound 5k (IC50 1.9μM) was even 5-fold higher than that of galantamine. In addition, the target compounds showed pronounced antioxidant ability and neuroprotective property, especially against the ROS-induced toxicity. Notably, the neuroprotective effect of 5k was obviously superior to that of the mixture of ferulic acid and carbazole, indicating the therapeutic effect of the hybrid compound is better than the combination administration of the corresponding mixture. Copyright © 2016 Elsevier Ltd. All rights reserved.

  12. Cholinesterases in Gambusia yucatana: Biochemical Characterization and its Relationship with Sex and Total Length.

    PubMed

    Rodríguez-Fuentes, Gabriela; Marín-López, Valeria; Hernández-Márquez, Esperanza

    2016-12-01

    Since several reports have indicated that cholinesterases (ChE) type and distribution is species specific and that in some species there is a relationship among gender, size and ChE activities, characterization has been suggested. The aim of the present study was to characterize the ChE present in head and muscle of Gambusia yucatana (using selective substrates and inhibitors) and to find its relationship with total length or gender. Results indicated that the ChE present in G. yucatana is an acetylcholinesterase (AChE) with high sensitivity to BW284C51 and an atypical smaller Km with butyrylthiocholine. Scatterplots indicated that there is no linearity between total length and AChE in male or female wild mosquitofish. There were no sex differences in AChE activities. Results indicated significant differences between a single collection site in the Yucatan peninsula and depurated organisms. This study emphasized the importance of characterizing ChE before usage in biomonitoring.

  13. Role of glutamate-199 in the aging of cholinesterase. (Reannouncement with new availability information)

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Saxena, A.; Doctor, B.P.; Maxwell, D.M.

    1993-11-30

    Aging of organophosphate-conjugated acetylcholinesterase results from the loss of an alkoxy group with concomitant stabilization of the conjugate to spontaneous or nucleophile-induced deacylation. We have examined the kinetics of aging in a pinacolylmethylphosphonofluoridate (soman)-inhibited mutant enzyme in which the glutamate (E199) located at the amino-terminal to the active-site sense (S200) was converted to glutamine (Q). For wild type enzyme, the soman-acetylcholinesterase conjugate aged immediately, giving rise to a form of enzyme resistant to reactivation by oximes. In contrast, the E199Q mutant enzyme was largely resistant to aging and could be reactivated by oximes. Since the pH dependence for aging wasmore » not altered appreciably, the primary influence of the loss of charge appears to be on the intrinsic rate of aging. The negative charge on E199 likely imparts an inductive effect on the conjugated organophosphate to facilitate removal of the alkoxy group. Cholinesterases, Aging, Organophosphate.« less

  14. Recovery study of cholinesterases and neurotoxic signs in the non-target freshwater invertebrate Chilina gibbosa after an acute exposure to an environmental concentration of azinphos-methyl.

    PubMed

    Cossi, Paula Fanny; Beverly, Boburg; Carlos, Luquet; Kristoff, Gisela

    2015-10-01

    Azinphos-methyl belongs to the class of organophosphate insecticides which are recognized for their anticholinesterase action. It is one of the most frequently used insecticides in the Upper Valley of Río Negro and Río Neuquén in Argentina, where agriculture represents the second most important economic activity. It has been detected in water from this North Patagonian region throughout the year and the maximum concentration found was 22.48 μg L(-1) during the application period. Chilina gibbosa is a freshwater gastropod widely distributed in South America, particularly in Patagonia, Argentina and in Southern Chile. Toxicological studies performed with C. gibbosa in our laboratory have reported neurotoxicity signs and cholinesterase inhibition after exposure to azinphos-methyl for 48 h. Recovery studies together with characterization of the enzyme and sensitivity of the enzyme to pesticides can improve the toxicological evaluation. However, little is known about recovery patterns in organisms exposed to organophosphates. The aim of the present work was to evaluate the recovery capacity (during 21 days in pesticide-free water) of cholinesterase activity and neurotoxicity in C. gibbosa after 48 h of exposure to azinphos-methyl. Also, lethality and carboxylesterase activity were registered during the recovery period. Regarding enzyme activities, after a 48-h exposure to 20 μg L(-1) of azinphos-methyl, cholinesterases showed an inhibition of 85% with respect to control, while carboxylesterases were not affected. After 21 days in pesticide-free water, cholinesterases continued to be inhibited (70%). Severe neurotoxicity signs were observed after exposure: 82% of the snails presented lack of adherence to vessels, 11% showed weak adherence, and 96% exhibited an abnormal protrusion of the head-foot region from shell. After 21 days in pesticide-free water, only 15% of the snails presented severe signs of neurotoxicity. However, during the recovery period significant

  15. The cholinesterase variants found in some African tribes living in Rhodesia.

    PubMed

    Whittaker, M; Lowe, R F

    1976-01-01

    Blood samples from 1,614 Africans living in Rhodesia have been phenotyped for the cholinesterase variants at the E1 and E2 loci. 24% of the African population were non-Rhodesian by birth. 1,227 Rhodesians aligned themselves to 20 tribes, 191 Malawians to 8 tribes. 162 Mozambique Africans to 9 tribes and 34 Zambians to 8 tribes. A high frequency of 0.036 for the Ef1 gene, which varies from tribe to tribe, has been found in Rhodesian and Malawian Africans. Similar high frequencies for this gene are recorded for Zambian (0.045) and Mozambique Africans (0.034). The frequencies of the Es1 gene in these groups are 0.013 (Rhodesian), 0.009 (Malawian), and 0.016 (Mozambique African). The small Zambian sample showed evidence for neither the Es1 nor the C5+ electrophoretic variant. The absence of the Ea1 gene in the 1,613 Africans provides additional evidence of the rarity of this gene in negroid populations. The frequency of the C5+ variant in Rhodesian, Malawian and Mozambique Africans, although varying from tribe to tribe within the range of 0-8%, averages 3% in each group. These represent low frequencies for this variant when compared to other populations. No rare or 'private' electrophoretic variant has been found.

  16. Microwave-assisted synthesis of novel purine nucleosides as selective cholinesterase inhibitors.

    PubMed

    Schwarz, S; Csuk, R; Rauter, A P

    2014-04-21

    Alzheimer's disease (AD), the most common form of senile dementia, is characterized by high butyrylcholinesterase (BChE) levels in the brain in later AD stages, for which no treatment is available. Pursuing our studies on selective BChE inhibitors, that may contribute to understand the role of this enzyme in disease progression, we present now microwave-assisted synthesis and anticholinesterase activity of a new nucleoside series embodying 6-chloropurine or 2-acetamido-6-chloropurine linked to D-glucosyl, D-galactosyl and D-mannosyl residues. It was designed to assess the contribution of sugar stereochemistry, purine structure and linkage to the sugar for cholinesterase inhibition efficiency and selectivity. Compounds were subjected to Ellman's assay and their inhibition constants determined. The α-anomers were the most active compounds, while selectivity for BChE or acetylcholinesterase (AChE) inhibition could be tuned by the purine base, by the glycosyl moiety and by N(7)-ligation. Some of the nucleosides were far more potent than the drug galantamine, and the most promising competitive and selective BChE inhibitor, the N(7)-linked 2-acetamido-α-D-mannosylpurine, showed a Ki of 50 nM and a selectivity factor of 340 fold for BChE over AChE.

  17. Molecular perception of interactions between bis(7)tacrine and cystamine-tacrine dimer with cholinesterases as the promising proposed agents for the treatment of Alzheimer's disease.

    PubMed

    Eslami, Mahboobeh; Hashemianzadeh, Seyed Majid; Bagherzadeh, Kowsar; Seyed Sajadi, Seyed Abolfazl

    2016-01-01

    The infamous chronic neurodegenerative disease, Alzheimer's, that starts with short-term memory loss and eventually leads to gradual bodily function decline which has been attributed to the deficiency in brain neurotransmitters, acetylcholine, and butylcholine. As a matter of fact, design of compounds that can inhibit cholinesterases activities (acetylcholinesterase and butylcholinesterase) has been introduced as an efficient method to treat Alzheimer's. Among proposed compounds, bis(7)tacrine (B7T) is recognized as a noteworthy suppressor for Alzheimer's disease. Recently a new analog of B7T, cystamine-tacrine dimer is offered as an agent to detain Alzheimer's complications, even better than the parent compound. In this study, classical molecular dynamic simulations have been employed to take a closer look into the modes of interactions between the mentioned ligands and both cholinesterase enzymes. According to our obtained results, the structural differences in the target enzymes active sites result in different modes of interactions and inhibition potencies of the ligands against both enzymes. The obtained information can help to investigate those favorable fragments in the studied ligands skeletons that have raised the potency of the analog in comparison with the parent compound to design more potent multi target ligands to heal Alzheimer's disease.

  18. Inhibition of human carboxylesterases hCE1 and hiCE by cholinesterase inhibitors.

    PubMed

    Tsurkan, Lyudmila G; Hatfield, M Jason; Edwards, Carol C; Hyatt, Janice L; Potter, Philip M

    2013-03-25

    Carboxylesterases (CEs) are ubiquitously expressed proteins that are responsible for the detoxification of xenobiotics. They tend to be expressed in tissues likely to be exposed to such agents (e.g., lung and gut epithelia, liver) and can hydrolyze numerous agents, including many clinically used drugs. Due to the considerable structural similarity between cholinesterases (ChE) and CEs, we have assessed the ability of a series of ChE inhibitors to modulate the activity of the human liver (hCE1) and the human intestinal CE (hiCE) isoforms. We observed inhibition of hCE1 and hiCE by carbamate-containing small molecules, including those used for the treatment of Alzheimer's disease. For example, rivastigmine resulted in greater than 95% inhibition of hiCE that was irreversible under the conditions used. Hence, the administration of esterified drugs, in combination with these carbamates, may inadvertently result in decreased hydrolysis of the former, thereby limiting their efficacy. Therefore drug:drug interactions should be carefully evaluated in individuals receiving ChE inhibitors. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  19. Inhibition of human carboxylesterases hCE1 and hiCE by cholinesterase inhibitors

    PubMed Central

    Tsurkan, Lyudmila G.; Hatfield, M. Jason; Edwards, Carol C.; Hyatt, Janice L.; Potter, Philip M.

    2012-01-01

    Carboxylesterases (CEs) are ubiquitously expressed proteins that are responsible for the detoxification of xenobiotics. They tend to be expressed in tissues likely to be exposed to such agents (e.g., lung and gut epithelia, liver) and can hydrolyze numerous agents, including many clinically used drugs. Due to the considerable structural similarity between cholinesterases (ChE) and CEs, we have assessed the ability of a series of ChE inhibitors to modulate the activity of the human liver (hCE1) and the human intestinal CE (hiCE) isoforms, We observed inhibition of hCE1 and hiCE by carbamate-containing small molecules, including those used for the treatment of Alzheimer’s disease. For example, rivastigmine resulted in greater than 95% inhibition of hiCE that was irreversible under the conditions used. Hence, the administration of esterified drugs, in combination with these carbamates, may inadvertently result in decreased hydrolysis of the former, thereby limiting their efficacy. Therefore drug:drug interactions should be carefully evaluated in individuals receiving ChE inhibitors. PMID:23123248

  20. Coumarin derivatives bearing benzoheterocycle moiety: synthesis, cholinesterase inhibitory, and docking simulation study

    PubMed Central

    Hirbod, Kimia; Jalili-baleh, Leili; Nadri, Hamid; ebrahimi, Seyed esmaeil Sadat; Moradi, Alireza; Pakseresht, Bahar; Foroumadi, Alireza; Shafiee, Abbas; Khoobi, Mehdi

    2017-01-01

    Objective(s): To investigate the efficiency of a novel series of coumarin derivatives bearing benzoheterocycle moiety as novel cholinesterase inhibitors. Materials and Methods: Different 7-hydroxycoumarin derivatives were synthesized via Pechmann or Knoevenagel condensation and conjugated to different benzoheterocycle (8-hydroxyquinoline, 2-mercaptobenzoxazole or 2-mercaptobenzimidazole) using dibromoalkanes 3a-m: Final compounds were evaluated against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) by Ellman’s method. Kinetic study of AChE inhibition and ligand-protein docking simulation were also carried out for the most potent compound 3b. Results: Some of the compounds revealed potent and selective activity against AChE. Compound 3b containing the quinoline group showed the best activity with an IC50 value of 8.80 μM against AChE. Kinetic study of AChE inhibition revealed the mixed-type inhibition of the enzyme by compound 3b. Ligand-protein docking simulation also showed that the flexibility of the hydrophobic five carbons linker allows the quinoline ring to form π-π interaction with Trp279 in the PAS. Conclusion: We suggest these synthesized compounds could become potential leads for AChE inhibition and prevention of AD symptoms. PMID:28868119

  1. Diagnosis of anticholinesterase poisoning in birds: Effects of environmental temperature and underfeeding on cholinesterase activity

    USGS Publications Warehouse

    Rattner, B.A.

    1982-01-01

    Brain cholinesterase (ChE) activity has been used extensively to monitor exposure to organophosphorus (OP) and carbamate (CB) insecticides in wild birds. A series of factorial experiments was conducted to assess the extent to which noncontaminant-related environmental conditions might affect brain ChE activity and thereby confound the diagnosis of OP and CB intoxication. Underfeeding (restricting intake to 50% of control for 21 d or fasting for 1-3 d) or exposure to elevated temperature (36 + 1?C for 1 d) caused only slight reductions (10-17%) in brain AChE activity in adult male Japanese quail (Coturnix coturnix japonica). This degree of 'reduction' in brain AChE activity is considerably less than the 50% 'inhibition' criterion employed in the diagnosis of insecticide-induced mortality, but nevertheless approaches the 20% 'inhibition' level used as a conservative estimate of sublethal exposure to a known insecticide application.

  2. Blood cholinesterase activity levels of farmers in winter and hot season of Mae Taeng District, Chiang Mai Province, Thailand.

    PubMed

    Hongsibsong, Surat; Kerdnoi, Tanyaporn; Polyiem, Watcharapon; Srinual, Niphan; Patarasiriwong, Vanvimol; Prapamontol, Tippawan

    2018-03-01

    Organophosphate and carbamate pesticides have been widely used by farmers for crop protection and pest control. Inhibition of acetylcholinesterase (AChE) in erythrocyte and butyrylcholinesterase (BChE) in plasma is the predominant toxic effect of organophosphate and carbamate pesticides. Mae Taeng District, Chiang Mai Province, is one of the large areas of growing vegetables and fruits. Due to their regular exposure to these pesticides, the farmers are affected by this toxicity. The objective of the study was to examine the AChE and the BChE activity levels in the blood of 102 farmers for comparison of exposure in two cropping seasons, winter and hot. Blood samples were collected in December 2013 (winter) and April-June 2014 (hot). A total of 102 farmers joined the study, represented by 76 males (74.5 %) and 26 females (25.5 %). The age of most of the farmers was 53.4 ± 8.7 years. Out of 102, 21 farmers used carbamate pesticides. The results showed that the AChE and the BChE activity levels of all the farmers were 3.27 ± 0.84 Unit/mL and 2.15 ± 0.58 Unit/mL, respectively. The AChE and the BChE activity levels in males were 3.31 ± 0.88 Unit/mL and 1.97 ± 0.60 U/mL, respectively, during winter and 3.27 ± 0.82 Unit/mL and 2.15 ± 0.58 U/mL, respectively, during the hot season, and AChE and the BChE activity levels in females were 3.27 ± 0.82 U/mL and 2.44 ± 0.56 U/mL, respectively, during the hot season. The cholinesterase activity levels, both AChE and BChE, in the male farmers' blood had significant difference between the two seasons, while in the case of the female farmers, there was significant difference in the BChE activity levels, at p < 0.05. The BChE activity level was found to significantly correlate with self-spray (p < 0.05), which implies that the BChE activity decreased when they sprayed by themselves. The cholinesterase activity levels of the present study were lower than those of the other

  3. Crystal structures of human cholinesterases in complex with huprine W and tacrine: elements of specificity for anti-Alzheimer's drugs targeting acetyl- and butyryl-cholinesterase.

    PubMed

    Nachon, Florian; Carletti, Eugénie; Ronco, Cyril; Trovaslet, Marie; Nicolet, Yvain; Jean, Ludovic; Renard, Pierre-Yves

    2013-08-01

    The multifunctional nature of Alzheimer's disease calls for MTDLs (multitarget-directed ligands) to act on different components of the pathology, like the cholinergic dysfunction and amyloid aggregation. Such MTDLs are usually on the basis of cholinesterase inhibitors (e.g. tacrine or huprine) coupled with another active molecule aimed at a different target. To aid in the design of these MTDLs, we report the crystal structures of hAChE (human acetylcholinesterase) in complex with FAS-2 (fasciculin 2) and a hydroxylated derivative of huprine (huprine W), and of hBChE (human butyrylcholinesterase) in complex with tacrine. Huprine W in hAChE and tacrine in hBChE reside in strikingly similar positions highlighting the conservation of key interactions, namely, π-π/cation-π interactions with Trp86 (Trp82), and hydrogen bonding with the main chain carbonyl of the catalytic histidine residue. Huprine W forms additional interactions with hAChE, which explains its superior affinity: the isoquinoline moiety is associated with a group of aromatic residues (Tyr337, Phe338 and Phe295 not present in hBChE) in addition to Trp86; the hydroxyl group is hydrogen bonded to both the catalytic serine residue and residues in the oxyanion hole; and the chlorine substituent is nested in a hydrophobic pocket interacting strongly with Trp439. There is no pocket in hBChE that is able to accommodate the chlorine substituent.

  4. Outcome of Alzheimer's disease: potential impact of cholinesterase inhibitors.

    PubMed

    Gillette-Guyonnet, Sophie; Andrieu, Sandrine; Cortes, Frédéric; Nourhashemi, Fati; Cantet, Christelle; Ousset, Pierre-Jean; Reynish, Emma; Grandjean, Hélène; Vellas, Bruno

    2006-05-01

    Alzheimer's disease is fast becoming a major public health concern with serious economic consequences. The cholinesterase inhibitors (CEIs) offer some benefit in the symptomatic treatment of the disease. This study aims to investigate the effect of CEIs on three clinically relevant domains (rapid cognitive decline, institutionalization, and weight loss) in patients with Alzheimer's disease. A prospective observational study was performed in which a population of 455 Alzheimer's disease patients were recruited and followed up for at least 1 year between 1994 and 2002. Patients were reevaluated at 6 monthly intervals using standardized neurocognitive and geriatric evaluations in addition to complete clinical examination, standard paraclinical investigations, and recording of treatment received. The risk of rapid cognitive deterioration was significantly decreased in patients taking CEIs for at least 1 year compared to untreated patients (odds ratio [OR]=0.56, 95% confidence interval [CI], 0.34-0.93; p=.025). The potential benefit of CEI use was also found on institutionalization (OR=0.2, 95% CI, 0.08-0.48; p<.001) and weight loss (OR=0.56, 95% CI, 0.32-0.97; p=.039) after 1 year of follow-up. The special interest of this study is that all patients were recruited and followed in the same center with the same management care plan and the same medical team. This follow-up offers us a unique opportunity to compare the 1-year evolution of the disease in clinical practice before and after the marketing of CEIs and allows us to demonstrate a clinically significant improvement in patient outcome over time.

  5. Synthesis and discovery of highly functionalized mono- and bis-spiro-pyrrolidines as potent cholinesterase enzyme inhibitors.

    PubMed

    Kia, Yalda; Osman, Hasnah; Suresh Kumar, Raju; Basiri, Alireza; Murugaiyah, Vikneswaran

    2014-04-01

    Novel mono and bis spiropyrrolidine derivatives were synthesized via an efficient ionic liquid mediated, 1,3-dipolar cycloaddition methodology and evaluated in vitro for their AChE and BChE inhibitory activities in search for potent cholinesterase enzyme inhibitors. Most of the synthesized compounds displayed remarkable AChE inhibitory activities with IC50 values ranging from 1.68 to 21.85 μM, wherein compounds 8d and 8j were found to be most active inhibitors against AChE and BChE with IC50 values of 1.68 and 2.75 μM, respectively. Molecular modeling simulation on Torpedo californica AChE and human BChE receptors, showed good correlation between IC50 values and binding interaction template of the most active inhibitors docked into the active site of their relevant enzymes. Copyright © 2014 Elsevier Ltd. All rights reserved.

  6. Syntheses and characterization of novel oxoisoaporphine derivatives as dual inhibitors for cholinesterases and amyloid beta aggregation.

    PubMed

    Li, Yan-Ping; Ning, Fang-Xian; Yang, Meng-Bi; Li, Yong-Cheng; Nie, Min-Hua; Ou, Tian-Miao; Tan, Jia-Heng; Huang, Shi-Liang; Li, Ding; Gu, Lian-Quan; Huang, Zhi-Shu

    2011-05-01

    A series of 3-substituted (5c-5f, 6c-6f) and 4-substituted (10a-10g) oxoisoaporphine derivatives were synthesized. It was found that all these synthetic compounds had IC50 values at micro or nano molar range for cholinesterase inhibition, and most of them could inhibit amyloid β (Aβ) self-induced aggregation with inhibition ratio from 31.8% to 57.6%. The structure-activity relationship studies revealed that the derivatives with higher selectivity on AChE also showed better inhibition on Aβ self-induced aggregation. The results from cell toxicity study indicated that most quaternary methiodide salts had higher IC50 values than the corresponding non-quaternary compounds. This study provided potentially important information for further development of oxoisoaporphine derivatives as lead compounds for the treatment of Alzheimer's disease. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

  7. Black-bellied whistling duck (Dendrocygna autumnalis) brain cholinesterase characterization and diagnosis of anticholinesterase pesticide exposure in wild populations from Mexico.

    PubMed

    Osten, Jaime Rendón-von; Soares, Amadeu M V M; Guilhermino, Lucia

    2005-02-01

    Rice is the main crop in the subbasin of the fluvial lagoon system of Palizada River (FLSPR) in the state of Campeche, Mexico. The pesticides used to control pests of this crop mainly are carbofuran, chlorpyrifos, and glyphosate. Black-bellied whistling duck (Dendrocygna autumnalis) is an ecologically and economically important species in the area. This duck is consumed by local inhabitants throughout the year, despite its potential exposure to pesticides. Due to its feeding habits, abundance, and nutritional value, D. autumnalis is a good indicator of environmental contamination and a potential route of human exposure to organophosphate and carbamate pesticides. In this study, the brain cholinesterase (ChE) in the frontal cerebral cortex of autochthonous ducks was characterized. In addition, the potential of the three locally used pesticides and mixtures to inhibit ChE activity was investigated and the exposure of the wild duck population during intensive pesticide applications in rice fields was evaluated. We found that acetylcholinesterase (AChE) seems to be the predominant ChE form in the biological fraction analyzed. Carbofuran was the most potent ChE inhibitor of D. autumnalis brain ChE activity from the three pesticides analyzed. Cholinesterase inhibition after exposure to pesticide mixtures predominantly was due to carbofuran. A decrease (p < 0.05) in AChE activity (>30%) was apparent in wild ducks compared to reference ducks, with recovery of ChE inhibition in wild ducks occurring months later when no pesticides were applied in the field. Dendrocygna autumnalis brain ChE is a suitable parameter for inclusion in biomonitoring programs for both environmental protection and human safety.

  8. BRAIN CHOLINESTERASE INHIBITION AND DEPRESSION OF THE PHOTIC AFTER DISCHARGE (PHAD) OF FLASH EVOKED POTENTIALS (FEPS) IN LONG EVANS RATS FOLLOWING ACUTE OR REPEATED EXPOSURES TO A MIXTURE OF CARBARYL AND PROPOXUR.

    EPA Science Inventory

    Carbaryl and propoxur are N-methyl carbamate pesticides (NMCs) which are part of the EPA’s cumulative risk assessments for NMCs. These NMCs inhibit cholinesterase (ChE) activity and may lead to cholinergic disruption of CNS function. We used decreases in the PhAD of FEPs to indic...

  9. Novel multi-target-directed ligands for Alzheimer's disease: Combining cholinesterase inhibitors and 5-HT6 receptor antagonists. Design, synthesis and biological evaluation.

    PubMed

    Więckowska, Anna; Kołaczkowski, Marcin; Bucki, Adam; Godyń, Justyna; Marcinkowska, Monika; Więckowski, Krzysztof; Zaręba, Paula; Siwek, Agata; Kazek, Grzegorz; Głuch-Lutwin, Monika; Mierzejewski, Paweł; Bienkowski, Przemysław; Sienkiewicz-Jarosz, Halina; Knez, Damijan; Wichur, Tomasz; Gobec, Stanislav; Malawska, Barbara

    2016-11-29

    As currently postulated, a complex treatment may be key to an effective therapy for Alzheimer's disease (AD). Recent clinical trials in patients with moderate AD have shown a superior effect of the combination therapy of donepezil (a selective acetylcholinesterase inhibitor) with idalopirdine (a 5-HT 6 receptor antagonist) over monotherapy with donepezil. Here, we present the first report on the design, synthesis and biological evaluation of a novel class of multifunctional ligands that combines a 5-HT 6 receptor antagonist with a cholinesterase inhibitor. Novel multi-target-directed ligands (MTDLs) were designed by combining pharmacophores directed against the 5-HT 6 receptor (1-(phenylsulfonyl)-4-(piperazin-1-yl)-1H-indole) and cholinesterases (tacrine or N-benzylpiperidine analogues). In vitro evaluation led to the identification of tacrine derivative 12 with well-balanced potencies against the 5-HT 6 receptor (K b  = 27 nM), acetylcholinesterase and butyrylcholinesterase (IC 50 hAChE  = 12 nM, IC 50 hBuChE  = 29 nM). The compound also showed good in vitro blood-brain-barrier permeability (PAMPA-BBB assay), which was confirmed in vivo (open field study). Central cholinomimetic activity was confirmed in vivo in rats using a scopolamine-induced hyperlocomotion model. A novel class of multifunctional ligands with compound 12 as the best derivative in a series represents an excellent starting point for the further development of an effective treatment for AD. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  10. CHRNA7 Polymorphisms and Response to Cholinesterase Inhibitors in Alzheimer's Disease

    PubMed Central

    Weng, Pei-Hsuan; Chen, Jen-Hau; Chen, Ta-Fu; Sun, Yu; Wen, Li-Li; Yip, Ping-Keung; Chu, Yi-Min; Chen, Yen-Ching

    2013-01-01

    Background CHRNA7 encodes the α7 nicotinic acetylcholine receptor subunit, which is important to Alzheimer's disease (AD) pathogenesis and cholinergic neurotransmission. Previously, CHRNA7 polymorphisms have not been related to cholinesterase inhibitors (ChEI) response. Methods Mild to moderate AD patients received ChEIs were recruited from the neurology clinics of three teaching hospitals from 2007 to 2010 (n = 204). Nine haplotype-tagging single nucleotide polymorphisms of CHRNA7 were genotyped. Cognitive responders were those showing improvement in the Mini-Mental State Examination score ≧2 between baseline and 6 months after ChEI treatment. Results AD women carrying rs8024987 variants [GG+GC vs. CC: adjusted odds ratio (AOR) = 3.62, 95% confidence interval (CI) = 1.47–8.89] and GG haplotype in block1 (AOR = 3.34, 95% CI = 1.38–8.06) had significantly better response to ChEIs (false discovery rate <0.05). These variant carriers using galantamine were 11 times more likely to be responders than female non-carriers using donepezil or rivastigmine. Conclusion For the first time, this study found a significant association between CHRNA7 polymorphisms and better ChEI response. If confirmed by further studies, CHRNA7 polymorphisms may aid in predicting ChEI response and refining treatment choice. PMID:24391883

  11. Design, synthesis and evaluation of novel tacrine-coumarin hybrids as multifunctional cholinesterase inhibitors against Alzheimer's disease.

    PubMed

    Xie, Sai-Sai; Wang, Xiao-Bing; Li, Jiang-Yan; Yang, Lei; Kong, Ling-Yi

    2013-06-01

    A series of tacrine-coumarin hybrids (8a-t) were designed, synthesized and evaluated as multifunctional cholinesterase (ChE) inhibitors against Alzheimer's disease (AD). The screening results showed that most of them exhibited a significant ability to inhibit ChE and self-induced β-amyloid (Aβ) aggregation, and to act as metal chelators. Especially, 8f displayed the greatest ability to inhibit acetylcholinesterase (AChE, IC50 = 0.092 μM) and Aβ aggregation (67.8%, 20 μM). It was also a good butyrylcholinesterase inhibitor (BuChE, IC50 = 0.234 μM) and metal chelator. Besides, kinetic and molecular modeling studies indicated that 8f was a mixed-type inhibitor, binding simultaneously to active, peripheral and mid-gorge sites of AChE. These results suggested that 8f might be an excellent multifunctional agent for AD treatment. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  12. Side effects of low-dose pyridostigmine bromide are not related to cholinesterase inhibition.

    PubMed

    Cook, M R; Gerkovich, M M; Sastre, A; Graham, C

    2001-12-01

    Pretreatment with pyridostigmine bromide (PB) has become part of standard military procedures for protection against the effects of possible chemical warfare attack. The purpose of the work reported here was to quantify the type, intensity and frequency of side effects of low-dose PB, and to examine factors that predict the intensity and frequency of side effects. A double-blind, cross-over, placebo (PL)-controlled design was used. Of the 67 subjects, 33 received 30 mg PB every 8 h for 13 doses, and 34 received 60 mg on the same schedule. Order of PB and PL administration was counterbalanced. Overall, side effects were mild, even at the 60-mg dose level. More side effects were reported when volunteers were taking PB than when they were taking placebo. Women reported more symptoms than men. Neither cholinesterase inhibition nor plasma levels of PB predicted side effect scores during the PB week; the best predictor of side effect scores during the PB week was side effect scores during the PL week. PB is well tolerated by healthy young people, even when twice the recommended military dose is administered.

  13. Synthesis, crystal structure determination, biological screening and docking studies of N1-substituted derivatives of 2,3-dihydroquinazolin-4(1H)-one as inhibitors of cholinesterases.

    PubMed

    Sultana, Nargis; Sarfraz, Muhammad; Tanoli, Saba Tahir; Akram, Muhammad Safwan; Sadiq, Abdul; Rashid, Umer; Tariq, Muhammad Ilyas

    2017-06-01

    Pursuing the strategy of developing potent AChE inhibitors, we attempted to carry out the N 1 -substitution of 2,3-dihydroquinazolin-4(1H)-one core. A set of 32 N-alkylated/benzylated quinazoline derivatives were synthesized, characterized and evaluated for their inhibition against cholinesterases. N-alkylation of the series of the compounds reported previously (N-unsubstituted) resulted in improved activity. All the compounds showed inhibition of both enzymes in the micromolar to submicromolar range. Structure activity relationship (SAR) of the 32 derivatives showed that N-benzylated compounds possess good activity than N-alkylated compounds. N-benzylated compounds 2ad and 2af were found very active with their IC 50 values toward AChE in submicromolar range (0.8µM and 0.6µM respectively). Binding modes of the synthesized compounds were explored by using GOLD (Genetic Optimization for Ligand Docking) suit v5.4.1. Computational predictions of ADMET studies reveal that all the compounds have good pharmacokinetic properties with no AMES toxicity and carcinogenicity. Moreover, all the compounds are predicted to be absorbed in human intestine and also have the ability to cross blood brain barrier. Overall, the synthesized compounds have established a structural foundation for the design of new inhibitors of cholinesterase. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. In vitro sensitivity of cholinesterases and [3H]oxotremorine-M binding in heart and brain of adult and aging rats to organophosphorus anticholinesterases.

    PubMed

    Mirajkar, Nikita; Pope, Carey N

    2008-10-15

    Organophosphorus (OP) insecticides elicit toxicity via acetylcholinesterase inhibition, allowing acetylcholine accumulation and excessive stimulation of cholinergic receptors. Some OP insecticides bind to additional macromolecules including butyrylcholinesterase and cholinergic receptors. While neurotoxicity from OP anticholinesterases has been extensively studied, effects on cardiac function have received less attention. We compared the in vitro sensitivity of acetylcholinesterase, butyrylcholinesterase and [(3)H]oxotremorine-M binding to muscarinic receptors in the cortex and heart of adult (3 months) and aging (18 months) rats to chlorpyrifos, methyl parathion and their active metabolites chlorpyrifos oxon and methyl paraoxon. Using selective inhibitors, the great majority of cholinesterase in brain was defined as acetylcholinesterase, while butyrylcholinesterase was the major cholinesterase in heart, regardless of age. In the heart, butyrylcholinesterase was markedly more sensitive than acetylcholinesterase to inhibition by chlorpyrifos oxon, and butyrylcholinesterase in tissues from aging rats was more sensitive than enzyme from adults, possibly due to differences in A-esterase mediated detoxification. Relatively similar differences were noted in brain. In contrast, acetylcholinesterase was more sensitive than butyrylcholinesterase to methyl paraoxon in both heart and brain, but no age-related differences were noted. Both oxons displaced [(3)H]oxotremorine-M binding in heart and brain of both age groups in a concentration-dependent manner. Chlorpyrifos had no effect but methyl parathion was a potent displacer of binding in heart and brain of both age groups. Such OP and age-related differences in interactions with cholinergic macromolecules may be important because of potential for environmental exposures to insecticides as well as the use of anticholinesterases in age-related neurological disorders.

  15. IN VITRO SENSITIVITY OF CHOLINESTERASES AND [3H]OXOTREMORINE-M BINDING IN HEART AND BRAIN OF ADULT AND AGING RATS TO ORGANOPHOSPHORUS ANTICHOLINESTERASES

    PubMed Central

    Mirajkar, Nikita; Pope, Carey N.

    2008-01-01

    Organophosphorus (OP) insecticides elicit toxicity via acetylcholinesterase inhibition, allowing acetylcholine accumulation and excessive stimulation of cholinergic receptors. Some OP insecticides bind to additional macromolecules including butyrylcholinesterase and cholinergic receptors. While neurotoxicity from OP anticholinesterases has been extensively studied, effects on cardiac function have received less attention. We compared the in vitro sensitivity of acetylcholinesterase, butyrylcholinesterase and [3H]oxotremorine-M binding to muscarinic receptors in the cortex and heart of adult (3 months) and aging (18 months) rats to chlorpyrifos, methyl parathion and their active metabolites chlorpyrifos oxon and methyl paraoxon. Using selective inhibitors, the great majority of cholinesterase in brain was defined as acetylcholinesterase, while butyrylcholinesterase was the major cholinesterase in heart, regardless of age. In the heart, butyrylcholinesterase was markedly more sensitive than acetylcholinesterase to inhibition by chlorpyrifos oxon, and butyrylcholinesterase in tissues from aging rats was more sensitive than enzyme from adults, possibly due to differences in A-esterase mediated detoxification. Relatively similar differences were noted in brain. In contrast, acetylcholinesterase was more sensitive than butyrylcholinesterase to methyl paraoxon in both heart and brain, but no age-related differences were noted. Both oxons displaced [3H]oxotremorine-M binding in heart and brain of both age groups in a concentration-dependent manner. Chlorpyrifos had no effect but methyl parathion was a potent displacer of binding in heart and brain of both age groups. Such OP and age-related differences in interactions with cholinergic macromolecules may be important because of potential for environmental exposures to insecticides as well as the use of anticholinesterases in age-related neurological disorders. PMID:18761328

  16. Cholinesterase inhibitory activity and chemical constituents of Stenochlaena palustris fronds at two different stages of maturity.

    PubMed

    Chear, Nelson Jeng-Yeou; Khaw, Kooi-Yeong; Murugaiyah, Vikneswaran; Lai, Choon-Sheen

    2016-04-01

    Stenochlaena palustris fronds are popular as a vegetable in Southeast Asia. The objectives of this study were to evaluate the anticholinesterase properties and phytochemical profiles of the young and mature fronds of this plant. Both types of fronds were found to have selective inhibitory effect against butyrylcholinesterase compared with acetylcholinesterase. However, different sets of compounds were responsible for their activity. In young fronds, an antibutyrylcholinesterase effect was observed in the hexane extract, which was comprised of a variety of aliphatic hydrocarbons, fatty acids, and phytosterols. In the mature fronds, inhibitory activity was observed in the methanol extract, which contained a series of kaempferol glycosides. Our results provided novel information concerning the ability of S. palustris to inhibit cholinesterase and its phytochemical profile. Further research to investigate the potential use of this plant against Alzheimer's disease is warranted, however, young and mature fronds should be distinguished due to their phytochemical differences. Copyright © 2016. Published by Elsevier B.V.

  17. Development of tacrine-bifendate conjugates with improved cholinesterase inhibitory and pro-cognitive efficacy and reduced hepatotoxicity.

    PubMed

    Cen, Juan; Guo, Huiyan; Hong, Chen; Lv, Jianwu; Yang, Yacheng; Wang, Ting; Fang, Dong; Luo, Wen; Wang, Chaojie

    2018-01-20

    A novel series of tacrine-bifendate (THA-DDB) conjugates (7a-e) were synthesized and evaluated as potential anti-Alzheimer's agents. These compounds showed potent cholinesterase and self-induced β-amyloid (Aβ) aggregation inhibitory activities. A Lineweaver-Burk plot and molecular modeling study showed that these compounds can target both catalytic active site (CAS) and peripheral anionic site (PAS) of acetylcholinesterase (AChE). The cytotoxicity of the conjugate 7d against PC12 and HepG2 cells and hepatotoxicity against human hepatocyte cell line (HL-7702) were found to be considerably less compared to THA. Moreover, treatment with 7d did not exhibit significant hepatotoxicity in mice. Finally, in vivo studies confirmed that 7d significantly ameliorates the cognitive performances of scopolamine-treated ICR mice. Therefore, 7d has high potential for the treatment of Alzheimer's disease and warrants further investigation. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  18. Metformin and Its Sulfenamide Prodrugs Inhibit Human Cholinesterase Activity.

    PubMed

    Markowicz-Piasecka, Magdalena; Sikora, Joanna; Mateusiak, Łukasz; Mikiciuk-Olasik, Elżbieta; Huttunen, Kristiina M

    2017-01-01

    The results of epidemiological and pathophysiological studies suggest that type 2 diabetes mellitus (T2DM) may predispose to Alzheimer's disease (AD). The two conditions present similar glucose levels, insulin resistance, and biochemical etiologies such as inflammation and oxidative stress. The diabetic state also contributes to increased acetylcholinesterase (AChE) activity, which is one of the factors leading to neurodegeneration in AD. The aim of this study was to assess in vitro the effects of metformin, phenformin, and metformin sulfenamide prodrugs on the activity of human AChE and butyrylcholinesterase (BuChE) and establish the type of inhibition. Metformin inhibited 50% of the AChE activity at micromolar concentrations (2.35  μ mol/mL, mixed type of inhibition) and seemed to be selective towards AChE since it presented low anti-BuChE activity. The tested metformin prodrugs inhibited cholinesterases (ChE) at nanomolar range and thus were more active than metformin or phenformin. The cyclohexyl sulfenamide prodrug demonstrated the highest activity towards both AChE (IC 50  = 890 nmol/mL, noncompetitive inhibition) and BuChE (IC 50  = 28 nmol/mL, mixed type inhibition), while the octyl sulfenamide prodrug did not present anti-AChE activity, but exhibited mixed inhibition towards BuChE (IC 50  = 184 nmol/mL). Therefore, these two bulkier prodrugs were concluded to be the most selective compounds for BuChE over AChE. In conclusion, it was demonstrated that biguanides present a novel class of inhibitors for AChE and BuChE and encourages further studies of these compounds for developing both selective and nonselective inhibitors of ChEs in the future.

  19. Novel 16-substituted bifunctional derivatives of huperzine B: multifunctional cholinesterase inhibitors

    PubMed Central

    Shi, Yu-fang; Zhang, Hai-yan; Wang, Wei; Fu, Yan; Xia, Yu; Tang, Xi-can; Bai, Dong-lu; He, Xu-chang

    2009-01-01

    Aim: To design novel bifunctional derivatives of huperzine B (HupB) based on the concept of dual binding site of acetylcholinesterase (AChE) and evaluate their pharmacological activities for seeking new drug candidates against Alzheimer's disease (AD). Methods: Novel 16-substituted bifunctional derivatives of HupB were synthesized through chemical reactions. The inhibitory activities of the derivatives toward AChE and butyrylcholinesterase (BuChE) were determined in vitro by modified Ellman's method. Cell viability was quantified by the reduction of MTT. Results: A new preparative method was developed for the generation of 16-substituted derivatives of HupB, and pharmacological trials indicated that the derivatives were multifunctional cholinesterase inhibitors targeting both AChE and BuChE. Among the derivatives tested, 9c, 9e, 9f, and 9i were 480 to 1360 times more potent as AChE inhibitors and 370 to 1560 times more potent as BuChE inhibitors than the parent HupB. Further preliminary pharmacological trials of derivatives 9c and 9i were performed, including examining the mechanism of AChE inhibition, the substrate kinetics of the enzyme inhibition, and protection against hydrogen peroxide (H2O2)-induced cytotoxicity in PC12 cells. Conclusion: Preliminary pharmacological evaluation indicated that 16-substituted derivatives of HupB, particularly 9c and 9i, would be potentially valuable new drug candidates for AD therapy, and further exploration is needed to evaluate their pharmacological and clinical efficacies. PMID:19578388

  20. Pharmacophore-based design and discovery of (-)-meptazinol carbamates as dual modulators of cholinesterase and amyloidogenesis.

    PubMed

    Xie, Qiong; Zheng, Zhaoxi; Shao, Biyun; Fu, Wei; Xia, Zheng; Li, Wei; Sun, Jian; Zheng, Wei; Zhang, Weiwei; Sheng, Wei; Zhang, Qihong; Chen, Hongzhuan; Wang, Hao; Qiu, Zhuibai

    2017-12-01

    Multifunctional carbamate-type acetylcholinesterase (AChE) inhibitors with anti-amyloidogenic properties like phenserine are potential therapeutic agents for Alzheimer's disease (AD). We reported here the design of new carbamates using pharmacophore model strategy to modulate both cholinesterase and amyloidogenesis. A five-feature pharmacophore model was generated based on 25 carbamate-type training set compounds. (-)-Meptazinol carbamates that superimposed well upon the model were designed and synthesized, which exhibited nanomolar AChE inhibitory potency and good anti-amyloidogenic properties in in vitro test. The phenylcarbamate 43 was highly potent (IC 50 31.6 nM) and slightly selective for AChE, and showed low acute toxicity. In enzyme kinetics assay, 43 exhibited uncompetitive inhibition and reacted by pseudo-irreversible mechanism. 43 also showed amyloid-β (Aβ) lowering effects (51.9% decrease of Aβ 42 ) superior to phenserine (31% decrease of total Aβ) in SH-SY5Y-APP 695 cells at 50 µM. The dual actions of 43 on cholinergic and amyloidogenic pathways indicated potential uses as symptomatic and disease-modifying agents.

  1. Preparation, in vitro screening and molecular modelling of symmetrical 4-tert-butylpyridinium cholinesterase inhibitors--analogues of SAD-128.

    PubMed

    Musilek, Kamil; Roder, Jan; Komloova, Marketa; Holas, Ondrej; Hrabinova, Martina; Pohanka, Miroslav; Dohnal, Vlastimil; Opletalova, Veronika; Kuca, Kamil; Jung, Young-Sik

    2011-01-01

    Carbamate inhibitors (e.g., pyridostimine bromide) are used as a pre-exposure treatment for the prevention of organophosphorus poisoning. They work by blocking acetylcholinesterase's (AChE) native function and thus protect AChE against irreversible inhibition by organophosphorus compounds. However, carbamate inhibitors are known for many undesirable side-effects related to the carbamylation of AChE. In this Letter, 19 analogues of SAD-128 were prepared and evaluated as cholinesterase inhibitors. The screening results showed promising inhibitory ability of four compounds better to used standards (pralidoxime, obidoxime, BW284c51, ethopropazine, SAD-128). Four most promising compounds were selected for further molecular docking studies. The SAR was stated from obtained data. The former receptor studies were reported and discussed. The further in vivo studies were recommended in the view of OP pre-exposure treatment. Copyright © 2010 Elsevier Ltd. All rights reserved.

  2. Profiling Cholinesterase Adduction: A High-Throughput Prioritization Method for Organophosphate Exposure Samples

    PubMed Central

    Carter, Melissa D.; Crow, Brian S.; Pantazides, Brooke G.; Watson, Caroline M.; deCastro, B. Rey; Thomas, Jerry D.; Blake, Thomas A.; Johnson, Rudolph C.

    2017-01-01

    A high-throughput prioritization method was developed for use with a validated confirmatory method detecting organophosphorus nerve agent exposure by immunomagnetic separation-HPLC-MS/MS. A ballistic gradient was incorporated into this analytical method in order to profile unadducted butyrylcholinesterase (BChE) in clinical samples. With Zhang, et al. 1999’s Z′-factor of 0.88 ± 0.01 (SD) of control analytes and Z-factor of 0.25 ± 0.06 (SD) of serum samples, the assay is rated an “excellent assay” for the synthetic peptide controls used and a “double assay” when used to prioritize clinical samples. Hits, defined as samples containing BChE Ser-198 adducts or no BChE present, were analyzed in a confirmatory method for identification and quantitation of the BChE adduct, if present. The ability to prioritize samples by highest exposure for confirmatory analysis is of particular importance in an exposure to cholinesterase inhibitors such as organophosphorus nerve agents where a large number of clinical samples may be collected. In an initial blind screen, 67 out of 70 samples were accurately identified giving an assay accuracy of 96% and yielded no false negatives. The method is the first to provide a high-throughput prioritization assay for profiling adduction of Ser-198 BChE in clinical samples. PMID:23954929

  3. Australian population trends and disparities in cholinesterase inhibitor use, 2003 to 2010.

    PubMed

    Zilkens, Renate R; Duke, Janine; Horner, Barbara; Semmens, James B; Bruce, David G

    2014-05-01

    The Australian Pharmaceutical Benefits Scheme (PBS) first subsidized cholinesterase inhibitors (CEIs) for Alzheimer's disease in 2001, introducing a novel therapy for a previously untreatable common condition. This study aims to determine Australian rates of CEI use and to assess equality of access to treatment based on socioeconomic status and geographic remoteness. Pharmaceutical claims records were used to identify all Australians prescribed CEIs between January 2003 and December 2010. Age-standardized and sex-adjusted index prescription rates were derived using the total Australian population as the denominator to examine temporal trends and the impacts of socioeconomic and geographic disadvantage on CEI index prescription rates. Index prescription rates peaked in 2004 at 92.5 per 100,000 person-years, declining to between 70.2 and 73.5 for years 2006 to 2010. Rates were highest in the 85- to 89-year age group and 2.6-fold higher in the least socioeconomic disadvantaged population when compared with the most disadvantaged population. In major cities in Australia, index prescription rates were 1.4 to 1.7 times greater compared with remote areas. Increasing geographic remoteness and socioeconomic disadvantage are associated with lower CEI index prescription rates, indicating inequities in the management of Alzheimer's disease in Australia. Copyright © 2014 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

  4. Novel brain-penetrating oximes for reactivation of cholinesterase inhibited by sarin and VX surrogates.

    PubMed

    Chambers, Janice E; Meek, Edward C; Chambers, Howard W

    2016-06-01

    Current oxime reactivators for organophosphate-inhibited cholinesterase (ChE) do not effectively cross the blood-brain barrier and therefore cannot restore brain ChE activity in vivo. Our laboratories have studied highly relevant sarin and VX surrogates, which differ from their respective nerve agents only in the leaving group and thereby leave ChE phosphylated with the same chemical moiety as sarin and VX. Our laboratories have developed novel substituted phenoxyalkyl pyridinium oximes that lead to reduced ChE inhibition in the brains of rats challenged with a high sublethal dosage of the sarin surrogate, whereas 2-PAM did not, using a paradigm designed to demonstrate brain penetration. In addition, treatment of rats with these novel oximes is associated with attenuation of seizure-like behavior compared to rats treated with 2-PAM, providing additional evidence that the oximes penetrate the blood-brain barrier. Further, some of the oximes provided 24-h survival superior to 2-PAM, and shortened the duration of seizure-like behavior when rats were challenged with lethal dosages of the sarin and VX surrogates, providing additional support for the conclusion that these oximes penetrate the brain. © 2016 New York Academy of Sciences.

  5. Recovery of brain and plasma cholinesterase activities in ducklings exposed to organophosphorus pesticides

    USGS Publications Warehouse

    Fleming, W.J.

    1981-01-01

    Brain and plasma cholinesterase (ChE) activities were determined for mallard ducklings (Anas platyrhynchos) exposed to dicrotophos and fenthion. Recovery rates of brain ChE did not differ between ducklings administered a single oral dose vs. a 2-week dietary dose of these organophosphates. Exposure to the organophosphates, followed by recovery of brain ChE, did not significantly affect the degree of brain ChE inhibition or the recovery of ChE activity at a subsequent exposure. Recovery of brain ChE activity followed the general model Y = a + b(logX) with rapid recovery to about 50% of normal, followed by a slower rate of recovery until normal ChE activity levels were attained. Fenthion and dicrotophos-inhibited brain ChE were only slightly reactivated in vitro by pyridine-2-aldoxime methiodide, which suggested that spontaneous reactivation was not a primary method of recovery of ChE activity. Recovery of brain ChE activity can be modeled for interpretation of sublethal inhibition of brain ChE activities in wild birds following environmental applications of organophosphates. Plasma ChE activity is inferior to brain ChE activity for environmental monitoring, because of its rapid recovery and large degree of variation among individuals.

  6. Synthesis and biological evaluation of 3-thiazolocoumarinyl Schiff-base derivatives as cholinesterase inhibitors.

    PubMed

    Raza, Rabia; Saeed, Aamer; Arif, Mubeen; Mahmood, Shamsul; Muddassar, Muhammad; Raza, Ahsan; Iqbal, Jamshed

    2012-10-01

    On the basis of the observed biological activity of the coumarins, a new set of 3-thiazolocoumarinyl Schiff-base derivatives with chlorine, hydroxy and methoxy functional group substitutions were designed and synthesized. These compounds were tested against acetylcholinesterase from Electrophorus electricus and butyrylcholinesterase from horse serum and their structure-activity relationship was established. Studies revealed them as the potential inhibitors of cholinesterase (acetylcholinesterase and butyrylcholinesterase). The 3f was found to be most potent against acetylcholinesterase with K(i) value of 1.05 ± 0.3 μM and 3l showed excellent inhibitory action against butyrylcholinesterase with K(i) value of 0.041 ± 0.002 μM. The synthesized compounds were also docked into the active sites of the homology models of acetylcholinesterase and butyrylcholinesterase to predict the binding modes of these compounds. It was predicted that most of the compounds have similar binding modes with reasonable binding affinities. Our docking studies have also shown that these synthesized compounds have better interaction patterns with butyrylcholinesterase over acetylcholinesterase. The main objective of the study was to develop new potent and selective compounds, which might be further optimized to prevent the progression of the Alzheimer's disease and could provide symptomatic treatment. © 2012 John Wiley & Sons A/S.

  7. Cholinesterase inhibitor (Altenuene) from an endophytic fungus Alternaria alternata: optimization, purification and characterization.

    PubMed

    Bhagat, J; Kaur, A; Kaur, R; Yadav, A K; Sharma, V; Chadha, B S

    2016-10-01

    The aim of this study was to screen endophytic fungi isolated from Vinca rosea for their potential to produce acetylcholinesterase (AChE) inhibitors. Endophytic fungi isolated from V. rosea (Catharanthus roseus), were screened for AChE inhibitor production using Ellman's method. Maximum inhibition against AChE (78%) was observed in an isolate VS-10, identified to be Alternaria alternata on morphological and molecular basis. The isolate also inhibited butyrylcholinesterase (73%). Significant increase (1·3 fold) was achieved after optimization of process parameters using one variable at time approach. The inhibitor was purified using chromatographic techniques. The structure elucidation of the inhibitor was carried out using spectroscopic techniques and was identified to be 'altenuene'. The purified inhibitor possessed antioxidant potential as revealed by dot blot assay. The insecticidal potential of purified inhibitor was evaluated by feeding Spodoptora litura on diet amended with inhibitor. It evinced significant larval mortality. Endophytic A. alternata can serve as a source of dual cholinesterase inhibitor 'altenuene' with significant antioxidant and insecticidal activity. This is the first report on acetylcholinestearse inhibitory activity of altenuene. Alternaria alternata has the potential to produce a dual ChE inhibitor with antioxidant activity useful in the treatment of neurodegenerative disorders and in agriculture as biocontrol agent. © 2016 The Society for Applied Microbiology.

  8. [The activity of blood cholinesterase in rats exposed to dimehypo].

    PubMed

    Wan, Weiguo; Xu, Mailing; Zou, Hejian; Lu, Ailing; Shen, Xinyu; Chen, Yuming

    2002-12-01

    To determine whether and to what degree the activity of cholinesterase(ChE) is inhibited by dimehypo at different doses of dimehypo [scientific name: 2-dimethylamine-1,3-bi(sodium hyposulfit)]. Rats were dosed with dimehypo or methamidophos orally, and were randomly divided into four subgroups according to the pesticide doses, which were 1/16, 1/8, 1/4 and 1/2 of LD50 respectively(the LD50 of dimethypo and methamidophos is 342 mg/kg and 20 mg/kg respectively). The activity of ChE in blood was determined before and 30 min, 1, 2, 4 and 24 h after exposure. The modified Ellman Method was employed to measure the activity of ChE. 1/16 LD50 dose of dimehypo did not affect the activity of ChE. When the dose increased, the activity of ChE decreased accordingly. 1/2 LD50 dose of dimehypo inhibited the activity of ChE by 35.9% compared with that of control group(P < 0.01). In rats dosed with methamidophos, even 1/16 LD50 dose inhibited the activity of ChE by 42.4% compared with that of control group. When the dose of methamidophos increased, the activity of ChE decreased accordingly. 1/2 LD50 dose of methamidophos inhibited the activity of ChE by 52.9%. The activity of ChE in the rats dosed with dimehypo at various doses was significantly lower than that in the rats dosed with corresponding doses of methamidophos(P < 0.01). Higher doses of dimehypo may inhibit the activity of ChE. However, as compared with methamidophos, dimehypo is a weaker inhibitor of ChE.

  9. Cholinesterase inhibitory activity of isoquinoline alkaloids from three Cryptocarya species (Lauraceae).

    PubMed

    Wan Othman, Wan Nurul Nazneem; Liew, Sook Yee; Khaw, Kooi Yeong; Murugaiyah, Vikneswaran; Litaudon, Marc; Awang, Khalijah

    2016-09-15

    Alzheimer's disease is the most common form of dementia among older adults. Acetylcholinesterase and butyrylcholinesterase are two enzymes involved in the breaking down of the neurotransmitter acetylcholine. Inhibitors for these enzymes have potential to prolong the availability of acetylcholine. Hence, the search for such inhibitors especially from natural products is needed in developing potential drugs for Alzheimer's disease. The present study investigates the cholinesterase inhibitory activity of compounds isolated from three Cryptocarya species towards acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Nine alkaloids were isolated; (+)-nornantenine 1, (-)-desmethylsecoantofine 2, (+)-oridine 3, (+)-laurotetanine 4 from the leaves of Cryptocarya densiflora BI., atherosperminine 5, (+)-N-methylisococlaurine 6, (+)-N-methyllaurotetanine 7 from the bark of Cryptocarya infectoria Miq., 2-methoxyatherosperminine 8 and (+)-reticuline 9 from the bark of Cryptocarya griffithiana Wight. In general, most of the alkaloids showed higher inhibition towards BChE as compared to AChE. The phenanthrene type alkaloid; 2-methoxyatherosperminine 8, exhibited the most potent inhibition against BChE with IC50 value of 3.95μM. Analysis of the Lineweaver-Burk (LB) plot of BChE activity over a range of substrate concentration suggested that 2-methoxyatherosperminine 8 exhibited mixed-mode inhibition with an inhibition constant (Ki) of 6.72μM. Molecular docking studies revealed that 2-methoxyatherosperminine 8 docked well at the choline binding site and catalytic triad of hBChE (butyrylcholinesterase from Homo sapiens); hydrogen bonding with Tyr 128 and His 438 residues respectively. Copyright © 2016 Elsevier Ltd. All rights reserved.

  10. Identifying motor and sensory myelinated axons in rabbit peripheral nerves by histochemical staining for carbonic anhydrase and cholinesterase activities

    NASA Technical Reports Server (NTRS)

    Riley, Danny A.; Sanger, James R.; Matloub, Hani S.; Yousif, N. John; Bain, James L. W.

    1988-01-01

    Carbonic anhydrase (CA) and cholinesterase (CE) histochemical staining of rabbit spinal nerve roots and dorsal root ganglia demonstrated that among the reactive myeliated axons, with minor exceptions, sensory axons were CA positive and CE negative whereas motor axons were CA negative and CE positive. The high specificity was achieved by adjusting reaction conditions to stain subpopulations of myelinated axons selectively while leaving 50 percent or so unstained. Fixation with glutaraldehyde appeared necessary for achieving selectivity. Following sciatic nerve transection, the reciprocal staining pattern persisted in damaged axons and their regenerating processes which formed neuromas within the proximal nerve stump. Within the neuromas, CA-stained sensory processes were elaborated earlier and in greater numbers than CE-stained regenerating motor processes. The present results indicate that histochemical axon typing can be exploited to reveal heterogeneous responses of motor and sensory axons to injury.

  11. Effects of motor patterns on water-soluble and membrane proteins and cholinesterase activity in subcellular fractions of rat brain tissue

    NASA Technical Reports Server (NTRS)

    Pevzner, L. Z.; Venkov, L.; Cheresharov, L.

    1980-01-01

    Albino rats were kept for a year under conditions of daily motor load or constant hypokinesia. An increase in motor activity results in a rise in the acetylcholinesterase activity determined in the synaptosomal and purified mitochondrial fractions while hypokinesia induces a pronounced decrease in this enzyme activity. The butyrylcholinesterase activity somewhat decreases in the synaptosomal fraction after hypokinesia but does not change under the motor load pattern. Motor load causes an increase in the amount of synaptosomal water-soluble proteins possessing an intermediate electrophoretic mobility and seem to correspond to the brain-specific protein 14-3-2. In the synaptosomal fraction the amount of membrane proteins with a low electrophoretic mobility and with the cholinesterase activity rises. Hypokinesia, on the contrary, decreases the amount of these membrane proteins.

  12. 7-MEOTA-donepezil like compounds as cholinesterase inhibitors: Synthesis, pharmacological evaluation, molecular modeling and QSAR studies.

    PubMed

    Korabecny, Jan; Dolezal, Rafael; Cabelova, Pavla; Horova, Anna; Hruba, Eva; Ricny, Jan; Sedlacek, Lukas; Nepovimova, Eugenie; Spilovska, Katarina; Andrs, Martin; Musilek, Kamil; Opletalova, Veronika; Sepsova, Vendula; Ripova, Daniela; Kuca, Kamil

    2014-07-23

    A novel series of 7-methoxytacrine (7-MEOTA)-donepezil like compounds was synthesized and tested for their ability to inhibit electric eel acetylcholinesterase (EeAChE), human recombinant AChE (hAChE), equine serum butyrylcholinesterase (eqBChE) and human plasmatic BChE (hBChE). New hybrids consist of a 7-MEOTA unit, representing less toxic tacrine (THA) derivative, connected with analogues of N-benzylpiperazine moieties mimicking N-benzylpiperidine fragment from donepezil. 7-MEOTA-donepezil like compounds exerted mostly non-selective profile in inhibiting cholinesterases of different origin with IC50 ranging from micromolar to sub-micromolar concentration scale. Kinetic analysis confirmed mixed-type inhibition presuming that these inhibitors are capable to simultaneously bind peripheral anionic site (PAS) as well as catalytic anionic site (CAS) of AChE. Molecular modeling studies and QSAR studies were performed to rationalize studies from in vitro. Overall, 7-MEOTA-donepezil like derivatives can be considered as interesting candidates for Alzheimer's disease treatment. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  13. Combination therapy with cholinesterase inhibitors and memantine for Alzheimer's disease: a systematic review and meta-analysis.

    PubMed

    Matsunaga, Shinji; Kishi, Taro; Iwata, Nakao

    2014-12-28

    We performed an updated meta-analysis of randomized controlled trials of combination therapy with cholinesterase inhibitors and memantine in patients with Alzheimer's disease. We reviewed cognitive function, activities of daily living, behavioral disturbance, global assessment, discontinuation rate, and individual side effects. Seven studies (total n=2182) were identified. Combination therapy significantly affected behavioral disturbance scores (standardized mean difference=-0.13), activity of daily living scores (standardized mean difference=-0.10), and global assessment scores (standardized mean difference=-0.15). In addition, cognitive function scores (standardized mean difference=-0.13, P=.06) exhibited favorable trends with combination therapy. The effects of combination therapy were more significant in the moderate-to-severe Alzheimer's disease subgroup in terms of all efficacy outcome scores. The discontinuation rate was similar in both groups, and there were no significant differences in individual side effects. Combination therapy was beneficial for the treatment of moderate-to-severe Alzheimer's disease in terms of cognition, behavioral disturbances, activities of daily living, and global assessment was well tolerated. © The Author 2015. Published by Oxford University Press on behalf of CINP.

  14. Tick Salivary Cholinesterase: A Probable Immunomodulator of Host-parasite Interactions.

    PubMed

    Temeyer, Kevin B; Tuckow, Alexander P

    2016-05-01

    The southern cattle tick, Rhipicephalus (Boophilus) microplus (Canestrini), is the most economically important cattle ectoparasite in the world. Rhipicephalus microplus and Rhipicephalus annulatus (Say) continue to threaten U.S. cattle producers despite eradication and an importation barrier based on inspection, dipping of imported cattle in organophosphate (OP) acaricide, and quarantine of infested premises. OP acaricides inhibit acetylcholinesterase (AChE), essential to tick central nervous system function. Unlike vertebrates, ticks possess at least three genes encoding AChEs, differing in amino acid sequence and biochemical properties. Genomic analyses of R. microplus and the related tick, Ixodes scapularis, suggest that ticks contain many genes encoding different AChEs. This work is the first report of a salivary cholinesterase (ChE) activity in R. microplus, and discusses complexity of the cholinergic system in ticks and significance of tick salivary ChE at the tick-host interface. It further provides three hypotheses that the salivary ChE plausibly functions 1) to reduce presence of potentially toxic acetylcholine present in the large bloodmeal imbibed during rapid engorgement, 2) to modulate the immune response (innate and/or acquired) of the host to tick antigens, and 3) to influence transmission and establishment of pathogens within the host animal. Ticks are vectors for a greater number and variety of pathogens than any other parasite, and are second only to mosquitoes (owing to malaria) as vectors of serious human disease. Saliva-assisted transmission (SAT) of pathogens is well-known; however, the salivary components participating in the SAT process remain to be elucidated. Published by Oxford University Press on behalf of Entomological Society of America 2016. This work is written by US Government employees and is in the public domain in the US.

  15. Partial protection from organophosphate-induced cholinesterase inhibition by metyrapone treatment.

    PubMed

    Swiercz, Radosław; Lutz, Piotr; Gralewicz, Sławomir; Grzelińska, Zofia; Piasecka-Zelga, Joanna; Wąsowicz, Wojciech

    2013-08-01

    Organophosphates are cholinesterase (ChE) inhibitors with worldwide use as insecticides. Stress response, evidenced by a dramatic and relatively long-lasting (several hours) rise in the plasma glucocorticoid concentration is an integral element of the organophosphate (OP) poisoning symptomatology. In rodents, corticosterone (CORT) is the main glucocorticoid. There are several reports suggesting a relationship between the stressor-induced rise in CORT concentration (the CORT response) and the activity of the cerebral and peripheral ChE. Thus, it seems reasonable to presume that, in OP intoxication, the rise in plasma CORT concentration may somehow affect the magnitude of the OP-induced ChE inhibition. Metyrapone (MET) [2-methyl-1,2-di(pyridin-3-yl)propan-1-one] blocks CORT synthesis by inhibiting steroid 11β-hydroxylase, thereby preventing the CORT response. Chlorfenvinphos (CVP) [2-chloro-1-(2,4-dichlorophenyl) ethenyl diethyl phosphate] is an organophosphate insecticide still in use in some countries. The purpose of the present work was to compare the CVP-induced effects - the rise of the plasma CORT concentration and the reduction in ChE activity - in MET-treated and MET-untreated rats. Chlorfenvinphos was administered once at 0.0, 0.5, 1.0 and 3.0 mg/kg i.p. Metyrapone, at 100 mg/kg i.p., was administered five times, at 24-h intervals. The first MET dose was given two hours before CVP. The following was observed in the MET-treated rats: i) no rise in plasma CORT concentration after the CVP administration, ii) a reduced inhibition and a faster restitution of blood and brain ChE activities. The results suggest that MET treatment may confer significant protection against at least some effects of OP poisoning. The likely mechanism of the protective MET action has been discussed.

  16. Pro-2-PAM Therapy for Central and Peripheral Cholinesterases

    PubMed Central

    DeMar, James C.; Clarkson, Edward D.; Ratcliffe, Ruthie H.; Campbell, Amy J.; Thangavelu, Sonia G.; Herdman, Christine A.; Leader, Haim; Schulz, Susan M.; Marek, Elizabeth; Medynets, Marie A.; Ku, Theresa C.; Evans, Sarah A.; Khan, Farhat A.; Owens, Roberta R.; Nambiar, Madhusoodana P.; Gordon, Richard K.

    2010-01-01

    Novel therapeutics to overcome the toxic effects of organophosphorus (OP) chemical agents are needed due to the documented use of OPs in warfare (e.g. 1980–1988 Iran/Iraq war) and terrorism (e.g. 1995 Tokyo subway attacks). Standard OP exposure therapy in the United States consists of atropine sulfate (to block muscarinic receptors), the acetylcholinesterase (AChE) reactivator (oxime) pralidoxime chloride (2-PAM), and a benzodiazepine anticonvulsant to ameliorate seizures. A major disadvantage is that quaternary nitrogen charged oximes, including 2-PAM, do not cross the blood brain barrier (BBB) to treat brain AChE. Therefore, we have synthesized and evaluated pro-2-PAM (a lipid permeable 2-PAM derivative) that can enter the brain and reactivate CNS AChE, preventing seizures in guinea pigs after exposure to OPs. The protective effects of the pro-2-PAM after OP exposure were shown using a) surgically-implanted radiotelemetry probes for electroencephalogram (EEG) b) neurohistopathology of brain, c) cholinesterase activities in the PNS and CNS, and d) survivability. The PNS oxime 2-PAM was ineffective at reducing seizures/status epilepticus (SE) in diisopropyl-fluorophosphate (DFP)-exposed animals. In contrast, pro-2-PAM significantly suppressed and then eliminated seizure activity. In OP-exposed guinea pigs, there was a significant reduction in neurological damage with pro-2-PAM, but not 2-PAM. Distinct regional areas of the brains showed significantly higher AChE activity 1.5 h after OP exposure in pro-2-PAM treated animals compared to the 2-PAM treated ones. However, blood and diaphragm showed similar AChE activities in animals treated with either oxime, as both 2-PAM and pro 2-PAM are PNS active oximes. In conclusion, pro-2-PAM can cross the BBB, is rapidly metabolized inside the brain to 2-PAM, and protects against OP-induced SE through restoration of brain AChE activity. Pro-2-PAM represents the first non-invasive means of administering a CNS therapeutic for

  17. Plasma cholinesterase levels of mountain plovers (Charadrius montanus) wintering in central California, USA

    USGS Publications Warehouse

    Iko, W.M.; Archuleta, A.S.; Knopf, F.L.

    2003-01-01

    Declines of over 60% in mountain plover (Charadrius montanus) populations over the past 30 years have made it a species of concern throughout its current range and a proposed species for listing under the U.S. Endangered Species Act. Wintering mountain plovers spend considerable time on freshly plowed agricultural fields where they may potentially be exposed to anticholinesterase pesticides. Because of the population status and wintering ecology of plovers, the objectives of our study were to use nondestructive methods to report baseline plasma cholinesterase (ChE) levels in free-ranging mountain plovers wintering in California, USA, and to assess whether sampled birds showed signs of ChE inhibition related to anticholinesterase chemical exposure. We compared plasma ChE activity for mountain plovers sampled from the Carrizo Plain (an area relatively free of anticholinesterase pesticide use) with similar measures for plovers from the Central Valley (where anticholinesterase pesticides are widely used). Analyses for ChE inhibition indicated that none of the plovers had been recently exposed to these chemicals. However, mean ChE levels of plovers from the Central Valley were significantly higher (32%) than levels reported for plovers from the Carrizo Plain. This result differs from our original assumption of higher exposure risk to mountain plovers in the Central Valley but does suggest that some effect is occurring in the ChE activity of mountain plovers wintering in California.

  18. Novel brain-penetrating oximes for reactivation of cholinesterase inhibited by sarin and VX surrogates

    PubMed Central

    Chambers, Janice E.; Meek, Edward C.; Chambers, Howard W.

    2016-01-01

    Current oxime reactivators for organophosphate-inhibited cholinesterase (ChE) do not effectively cross the blood–brain barrier and therefore cannot restore brain ChE activity in vivo. Our laboratories have studied highly relevant sarin and VX surrogates, which differ from their respective nerve agents only in the leaving group and thereby leave ChE phosphylated with the same chemical moiety as sarin and VX. Our laboratories have invented novel substituted phenoxyalkyl pyridinium oximes (U.S. Patent 9,227,937 B2) that lead to reduced ChE inhibition in the brains of rats challenged with a high sublethal dosage of the sarin surrogate, whereas 2-PAM did not, using a paradigm designed to demonstrate brain penetration. In addition, these novel oximes also showed an attenuation of seizure-like behavior compared to rats treated with 2-PAM, giving additional evidence of the ability of these oximes to penetrate the blood–brain barrier. Further, some of these oximes provided 24-hour survival superior to 2-PAM and shortened the duration of seizure-like behavior when rats were challenged with lethal dosages of the sarin and VX surrogates, providing additional support for the concept of these life-saving oximes penetrating the brain. PMID:27153507

  19. Simulating the impact of cholinesterase-inhibiting pesticides on non-target wildlife in irrigated crops

    USGS Publications Warehouse

    Pisani, J.M.; Grant, W.E.; Mora, M.A.

    2008-01-01

    We present a simulation model for risk assessment of the impact of insecticide inhibitors of cholinesterase (ChE) applied in irrigated agricultural fields on non-target wildlife. The model, which we developed as a compartment model based on difference equations (??t = 1 h), consists of six submodels describing the dynamics of (1) insecticide application, (2) insecticide movement into floodable soil, (3) irrigation and rain, (4) insecticide dissolution in water, (5) foraging and insecticide intake from water, and (6) ChE inhibition and recovery. To demonstrate application of the model, we simulated historical and "worst-case" scenarios of the impact of ChE-inhibiting insecticides on white-winged doves (Zenaida asiatica) inhabiting natural brushland adjacent to cotton and sugarcane fields in the Lower Rio Grande Valley of Texas, USA. Only when a rain event occurred just after insecticide application did predicted levels of ChE inhibition surpass the diagnostic level of 20% exposure. The present model should aid in assessing the effect of ChE-inhibiting insecticides on ChE activity of different species that drink contaminated water from irrigated agricultural fields, and in identifying specific situations in which the juxtaposition of environmental conditions and management schemes could result in a high risk to non-target wildlife. ?? 2007 Elsevier B.V. All rights reserved.

  20. Attenuation of MPTP-induced dopaminergic neurotoxicity by TV3326, a cholinesterase-monoamine oxidase inhibitor.

    PubMed

    Sagi, Yotam; Weinstock, Marta; Youdim, Moussa B H

    2003-07-01

    (R)-[(N-propargyl-(3R) aminoindan-5-yl) ethyl methyl carbamate] (TV3326) is a novel cholinesterase and brain-selective monoamine oxidase (MAO)-A/-B inhibitor. It was developed for the treatment of dementia co-morbid with extra pyramidal disorders (parkinsonism), and depression. On chronic treatment in mice it attenuated striatal dopamine depletion induced by MPTP and prevented the reduction in striatal tyrosine hydroxylase activity, like selective B and non-selective MAO inhibitors. TV3326 preferentially inhibits MAO-B in the striatum and hippocampus, and the degree of MAO-B inhibition correlates with the prevention of MPTP-induced dopamine depletion. Complete inhibition of MAO-B is not necessary for full protection from MPTP neurotoxicity. Unlike that seen after treatment with other MAO-A and -B inhibitors, recovery of striatal and hippocampal MAO-A and -B activities from inhibition by TV3326 did not show first-order kinetics. This has been attributed to the generation of a number of metabolites by TV3326 that cause differential inhibition of these enzymes. Inhibition of brain MAO-A and -B by TV3326 resulted in significant elevations of dopamine, noradrenaline and serotonin in the striatum and hippocampus. This may explain its antidepressant-like activity, resembling that of moclobemide in the forced-swim test in rats.

  1. The Antioxidant Additive Approach for Alzheimer's Disease Therapy: New Ferulic (Lipoic) Acid Plus Melatonin Modified Tacrines as Cholinesterases Inhibitors, Direct Antioxidants, and Nuclear Factor (Erythroid-Derived 2)-Like 2 Activators.

    PubMed

    Benchekroun, Mohamed; Romero, Alejandro; Egea, Javier; León, Rafael; Michalska, Patrycja; Buendía, Izaskun; Jimeno, María Luisa; Jun, Daniel; Janockova, Jana; Sepsova, Vendula; Soukup, Ondrej; Bautista-Aguilera, Oscar M; Refouvelet, Bernard; Ouari, Olivier; Marco-Contelles, José; Ismaili, Lhassane

    2016-11-10

    Novel multifunctional tacrines for Alzheimer's disease were obtained by Ugi-reaction between ferulic (or lipoic acid), a melatonin-like isocyanide, formaldehyde, and tacrine derivatives, according to the antioxidant additive approach in order to modulate the oxidative stress as therapeutic strategy. Compound 5c has been identified as a promising permeable agent showing excellent antioxidant properties, strong cholinesterase inhibitory activity, less hepatotoxicity than tacrine, and the best neuroprotective capacity, being able to significantly activate the Nrf2 transcriptional pathway.

  2. UHPLC-ESI-ORBITRAP-MS analysis of the native Mapuche medicinal plant palo negro (Leptocarpha rivularis DC. - Asteraceae) and evaluation of its antioxidant and cholinesterase inhibitory properties.

    PubMed

    Jiménez-González, Andrea; Quispe, Cristina; Bórquez, Jorge; Sepúlveda, Beatriz; Riveros, Felipe; Areche, Carlos; Nagles, Edgar; García-Beltrán, Olimpo; Simirgiotis, Mario J

    2018-12-01

    UHPLC/ESI/MS identification of organic compounds is the first step in the majority of screening techniques for the characterization of biologically active metabolites in natural sources. This paper describes a method for the fast identification and characterisation of secondary metabolites in Leptocarpha rivularis DC. (Palo negro) extracts by HPLC/UV (DAD)-Mass Spectrometry (HPLC/MS). The plant is used for the treatment of several diseases since pre-hispanic Mapuche times. Thirty-seven compounds were detected in the aqueous edible extract for the first time including 4 sesquiterpenes, 10 flavonoids, 9 oxylipins, 2 organic acids, and 11 phenolic acids. In addition, phenolic content antioxidant and cholinesterase inhibitory activities were measured for the first time using the edible infusion. The total polyphenol content of the infusion was 230.76 ± 2.5 mmol GAE/kg dry weight, while the antioxidant activity was 176.51 ± 28.84; 195.28 ± 4.83; and 223.92 ± 2.95 mmol TE/kg dry weight, for the DPPH, ABTS, and FRAP assays, respectively. The cholinesterase inhibitory activity was 7.38 ± 0.03 and 5.74 ± 0.06 mmol GALAE/kg, for the inhibition of acetylcholinesterase AChE and BChE, respectively, showing that this plant is a candidate for the isolation of compounds that can be useful for the treatment of neurodegenerative diseases. Furthermore, this plant could serve also as a raw material for the production of dietary supplements, due to its content of polyphenolic compounds.

  3. (-)-Meptazinol-melatonin hybrids as novel dual inhibitors of cholinesterases and amyloid-β aggregation with high antioxidant potency for Alzheimer's therapy.

    PubMed

    Cheng, Shaobing; Zheng, Wei; Gong, Ping; Zhou, Qiang; Xie, Qiong; Yu, Lining; Zhang, Peiyi; Chen, Liangkang; Li, Juan; Chen, Jianxing; Chen, Hailin; Chen, Hongzhuan

    2015-07-01

    The multifactorial pathogenesis of Alzheimer's disease (AD) implicates that multi-target-directed ligands (MTDLs) intervention may represent a promising therapy for AD. Amyloid-β (Aβ) aggregation and oxidative stress, two prominent neuropathological hallmarks in patients, play crucial roles in the neurotoxic cascade of this disease. In the present study, a series of novel (-)-meptazinol-melatonin hybrids were designed, synthesized and biologically characterized as potential MTDLs against AD. Among them, hybrids 7-7c displayed higher dual inhibitory potency toward cholinesterases (ChEs) and better oxygen radical absorbance capacity (ORAC) than the parental drugs. Furthermore, compound 7c could effectively inhibit Aβ self-aggregation, showed favorable safety and the blood-brain barrier (BBB) permeability. Therefore, 7c may serve as a valuable candidate that is worthy of further investigations in the treatment of AD. Copyright © 2015 Elsevier Ltd. All rights reserved.

  4. Butyryl-cholinesterase is related to muscle mass and strength. A new biomarker to identify elderly subjects at risk of sarcopenia.

    PubMed

    Cacciatore, Francesco; Della-Morte, David; Basile, Claudia; Curcio, Francesco; Liguori, Ilaria; Roselli, Mario; Gargiulo, Gaetano; Galizia, Gianluigi; Bonaduce, Domenico; Abete, Pasquale

    2015-01-01

    To determine the relationship between Butyryl-cholinesterase (α-glycoprotein synthesized in the liver, b-CHE) and muscle mass and strength. Muscle mass by bioimpedentiometer and muscle strength by grip strength were evaluated in 337 elderly subjects (mean age: 76.2 ± 6.7 years) admitted to comprehensive geriatric assessment. b-CHE levels were lower in sarcopenic than in nonsarcopenic elderly subjects (p < 0.01). Linear regression analysis demonstrated that b-CHE is linearly related with grip strength and muscular mass both in men and women (r = 0.45 and r = 0.33, p < 0.01; r = 0.55 and r = 0.39, p < 0.01; respectively). Multivariate analysis confirms this analysis. b-CHE is related to muscle mass and strength in elderly subjects. Thus, b-CHE may be considered to be a fair biomarker for identifying elderly subjects at risk of sarcopenia.

  5. Combination Therapy with Cholinesterase Inhibitors and Memantine for Alzheimer’s Disease: A Systematic Review and Meta-Analysis

    PubMed Central

    Kishi, Taro; Iwata, Nakao

    2015-01-01

    Background: We performed an updated meta-analysis of randomized controlled trials of combination therapy with cholinesterase inhibitors and memantine in patients with Alzheimer’s disease. Methods: We reviewed cognitive function, activities of daily living, behavioral disturbance, global assessment, discontinuation rate, and individual side effects. Results: Seven studies (total n=2182) were identified. Combination therapy significantly affected behavioral disturbance scores (standardized mean difference=−0.13), activity of daily living scores (standardized mean difference=−0.10), and global assessment scores (standardized mean difference=−0.15). In addition, cognitive function scores (standardized mean difference=−0.13, P=.06) exhibited favorable trends with combination therapy. The effects of combination therapy were more significant in the moderate-to-severe Alzheimer’s disease subgroup in terms of all efficacy outcome scores. The discontinuation rate was similar in both groups, and there were no significant differences in individual side effects. Conclusions: Combination therapy was beneficial for the treatment of moderate-to-severe Alzheimer’s disease in terms of cognition, behavioral disturbances, activities of daily living, and global assessment was well tolerated. PMID:25548104

  6. Intrahippocampal cholinesterase inhibition induces epileptogenesis in mice without evidence of neurodegenerative events.

    PubMed

    Pernot, F; Carpentier, P; Baille, V; Testylier, G; Beaup, C; Foquin, A; Filliat, P; Liscia, P; Coutan, M; Piérard, C; Béracochea, D; Dorandeu, F

    2009-09-15

    The mechanisms of epileptogenesis remain largely unknown and are probably diverse. The aim of this study was to investigate the role of focal cholinergic imbalance in epileptogenesis. To address this question, we monitored electroencephalogram (EEG) activity up to 12 weeks after the injection of a potent cholinesterase (ChE) inhibitor (soman) at different doses (0.53, 0.75, 1, 2, 2.8, 4 and 11 nmol) into the right dorsal hippocampus of C57BL/6 mice. Different parameters were used to choose the dose for a focal model of epileptogenesis (mainly electrographic patterns and peripheral ChE inhibition). The pattern of neuronal activation was studied by Fos immunohistochemistry (IHC). Brain damage was evaluated by hemalun-phloxin, neuronal nuclei antigen IHC and silver staining. Glial fibrillary acidic protein IHC was used to evaluate astroglial reaction. Finally, long-term behavioral consequences were characterized. At the highest dose (11 nmol), soman quickly evoked severe signs, including initial seizures and promoted epileptogenesis in the absence of tissue damage. With lower doses, late-onset seizures were evidenced, after 1-4 weeks depending on the dose, despite the absence of initial overt seizures and of brain damage. Only a weak astroglial reaction was observed. Following injection of 1 nmol, Fos changes were first evidenced in the ipsilateral hippocampus and then spread to extrahippocampal areas. A selective deficit in contextual fear conditioning was also evidenced two months after injection. Our data show that focal hypercholinergy may be a sufficient initial event to promote epilepsy and that major brain tissue changes (cellular damage, edema, neuroinflammation) are not necessary conditions.

  7. Evidence for inhibition of cholinesterases in insect and mammalian nervous systems by the insect repellent deet.

    PubMed

    Corbel, Vincent; Stankiewicz, Maria; Pennetier, Cédric; Fournier, Didier; Stojan, Jure; Girard, Emmanuelle; Dimitrov, Mitko; Molgó, Jordi; Hougard, Jean-Marc; Lapied, Bruno

    2009-08-05

    N,N-Diethyl-3-methylbenzamide (deet) remains the gold standard for insect repellents. About 200 million people use it every year and over 8 billion doses have been applied over the past 50 years. Despite the widespread and increased interest in the use of deet in public health programmes, controversies remain concerning both the identification of its target sites at the olfactory system and its mechanism of toxicity in insects, mammals and humans. Here, we investigated the molecular target site for deet and the consequences of its interactions with carbamate insecticides on the cholinergic system. By using toxicological, biochemical and electrophysiological techniques, we show that deet is not simply a behaviour-modifying chemical but that it also inhibits cholinesterase activity, in both insect and mammalian neuronal preparations. Deet is commonly used in combination with insecticides and we show that deet has the capacity to strengthen the toxicity of carbamates, a class of insecticides known to block acetylcholinesterase. These findings question the safety of deet, particularly in combination with other chemicals, and they highlight the importance of a multidisciplinary approach to the development of safer insect repellents for use in public health.

  8. Design, synthesis and evaluation of novel 7-aminoalkyl-substituted flavonoid derivatives with improved cholinesterase inhibitory activities.

    PubMed

    Luo, Wen; Chen, Ying; Wang, Ting; Hong, Chen; Chang, Li-Ping; Chang, Cong-Cong; Yang, Ya-Cheng; Xie, Song-Qiang; Wang, Chao-Jie

    2016-02-15

    A novel series of 7-aminoalkyl-substituted flavonoid derivatives 5a-5r were designed, synthesized and evaluated as potential cholinesterase inhibitors. The results showed that most of the synthesized compounds exhibited potent acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities at the micromolar range. Compound 2-(naphthalen-1-yl)-7-(8-(pyrrolidin-1-yl)octyloxy)-4H-chromen-4-one (5q) showed the best inhibitory activity (IC50, 0.64μM for AChE and 0.42μM for BChE) which were better than our previously reported compounds and the commercially available cholinergic agent Rivastigmine. The results from a Lineweaver-Burk plot indicated a mixed-type inhibition for compound 5q with AChE and BChE. Furthermore, molecular modeling study showed that 5q targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Besides, these compounds (5a-5r) did not affect PC12 and HepG2 cell viability at the concentration of 10μM. Consequently, these flavonoid derivatives should be further investigated as multipotent agents for the treatment of Alzheimer's disease. Copyright © 2015 Elsevier Ltd. All rights reserved.

  9. Evidence for inhibition of cholinesterases in insect and mammalian nervous systems by the insect repellent deet

    PubMed Central

    Corbel, Vincent; Stankiewicz, Maria; Pennetier, Cédric; Fournier, Didier; Stojan, Jure; Girard, Emmanuelle; Dimitrov, Mitko; Molgó, Jordi; Hougard, Jean-Marc; Lapied, Bruno

    2009-01-01

    Background N,N-Diethyl-3-methylbenzamide (deet) remains the gold standard for insect repellents. About 200 million people use it every year and over 8 billion doses have been applied over the past 50 years. Despite the widespread and increased interest in the use of deet in public health programmes, controversies remain concerning both the identification of its target sites at the olfactory system and its mechanism of toxicity in insects, mammals and humans. Here, we investigated the molecular target site for deet and the consequences of its interactions with carbamate insecticides on the cholinergic system. Results By using toxicological, biochemical and electrophysiological techniques, we show that deet is not simply a behaviour-modifying chemical but that it also inhibits cholinesterase activity, in both insect and mammalian neuronal preparations. Deet is commonly used in combination with insecticides and we show that deet has the capacity to strengthen the toxicity of carbamates, a class of insecticides known to block acetylcholinesterase. Conclusion These findings question the safety of deet, particularly in combination with other chemicals, and they highlight the importance of a multidisciplinary approach to the development of safer insect repellents for use in public health. PMID:19656357

  10. Effects of malathion, diazinon, and parathion on mallard embryo development and cholinesterase activity

    USGS Publications Warehouse

    Hoffman, D.J.; Eastin, W.C.

    1981-01-01

    The effects of external exposure of mallard (Anas platyrhynchos) eggs to malathion, diazinon, and parathion were examined using formulations and concentrations similar to field applications. Treatment with aqueous emulsion simulated exposure at the rate of 100 gal per acre (153 liters/hectare) with three to six different doses per compound with treatment at 3 and 8 days of embryonic development. Treatment with a nontoxic oil vehicle simulated exposure at the rate of 11 gal per acre (16.8 liters/hectare) with three to six different doses per compound. The order of embryotoxicity on a pounds-per-acre basis was parathion > diazinon > malathion with either vehicle. However, the potential hazard under conditions of up to five times the maximum field level of application was greater for malathion because of the high permissible level of application for malathion on certain crops. Parathion, the most embryotoxic of the three, had the most pronounced effects when an oil vehicle was used, as reflected by an LC50 of about 2 lb of active ingredient per acre, stunted growth, and a high frequency of malformations involving distortion of the axial skeleton, particularly in the cervical region. All three compounds resulted in significant depression of plasma and brain cholinesterase activity, but parathion caused the most depression throughout development, which was still apparent in hatchlings. Treatment with either distilled water or oil vehicle alone did not result in any of these effects seen with organophosphorous insecticides.

  11. Novel Cholinesterase Inhibitors Based on O-Aromatic N,N-Disubstituted Carbamates and Thiocarbamates.

    PubMed

    Krátký, Martin; Štěpánková, Šárka; Vorčáková, Katarína; Švarcová, Markéta; Vinšová, Jarmila

    2016-02-11

    Based on the presence of carbamoyl moiety, twenty salicylanilide N,N-disubstituted (thio)carbamates were investigated using Ellman's method for their ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). O-Aromatic (thio)carbamates exhibited weak to moderate inhibition of both cholinesterases with IC50 values within the range of 1.60 to 311.0 µM. IC50 values for BChE were mostly lower than those obtained for AChE; four derivatives showed distinct selectivity for BChE. All of the (thio)carbamates produced a stronger inhibition of AChE than rivastigmine, and five of them inhibited BChE more effectively than both established drugs rivastigmine and galantamine. In general, 5-chloro-2-hydroxy-N-[4-(trifluoromethyl)-phenyl]benzamide, 2-hydroxy-N-phenylbenzamide as well as N-methyl-N-phenyl carbamate derivatives led to the more potent inhibition. O-{4-Chloro-2-[(4-chlorophenyl)carbamoyl]phenyl} dimethylcarbamothioate was identified as the most effective AChE inhibitor (IC50 = 38.98 µM), while 2-(phenylcarbamoyl)phenyl diphenylcarbamate produced the lowest IC50 value for BChE (1.60 µM). Results from molecular docking studies suggest that carbamate compounds, especially N,N-diphenyl substituted representatives with considerable portion of aromatic moieties may work as non-covalent inhibitors displaying many interactions at peripheral anionic sites of both enzymes. Mild cytotoxicity for HepG2 cells and consequent satisfactory calculated selectivity indexes qualify several derivatives for further optimization.

  12. [Severity of the intoxications by cholinesterase inhibitor insecticides registered in the northwest of the state of Paraná, Brazil].

    PubMed

    de Oliveira, Magda Lúcia Félix; Buriola, Aline Aparecida

    2009-12-01

    This article has as objective the discussion of the severity of intoxications by cholinesterase inhibitor insecticides, which happened in the Northwest of Paraná, Brazil, starting from an exploratory descriptive study with retrospective analysis of epidemiological data sheets of the Intoxications Control Center in the University Hospital of Maringá, Paraná, Brazil, referring to patients intoxicated from January, 1994 to December 2005. 529 cases were analyzed, 168 (31,7%) for organophosphates and 167 (31,5%) for carbamate. The suicide attempt represented 257 cases (48,5%), the occupational exposure 140 (26,5%), and the accidental 124 (23,5%). Comparing the number of severe intoxications and deaths, it was verified from 100% of deaths to cases severe occupational exposure, 20% for the suicide attempt and 7,5% deaths for the accidental intoxications classified as severe. The high incidence of serious intoxication and mortality suggest preventive strategies in respect of the usage of the insecticides, aiming to restrict the indiscriminate access to these powerful toxic agents.

  13. Inhibition of Cholinesterases and Some Pro-Oxidant induced Oxidative Stress in Rats Brain by Two Tomato (Lycopersicon Esculentum) Varieties

    PubMed Central

    Oboh, G.; Bakare, O.O.; Ademosun, A.O.; Akinyemi, A.J.; Olasehinde, T.A.

    2015-01-01

    This study sought to investigate the effects of two tomato varieties [Lycopersicon esculentum Mill. var. esculentum (ESC) and Lycopersicon esculentum Mill. var. cerasiforme (CER)] on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities in vitro. Phenolics content, carotenoids characterisation, inhibition of Fe2+ and quinolinic acid-induced malondialdehyde (MDA) production in rats brain homogenate and NO* scavenging abilities were also assesed in addition to the AChE and BChE inhibition assays. There was no significant difference in the AChE inhibitory ability of the samples, while CER had significantly higher BChE inhibitory activity. Furthermore, the tomatoes inhibited Fe2+ and quinolinic acid-induced MDA production and further exhibited antioxidant activities through their NO* scavenging abilities. There was no significant difference in the phenolic content of the samples, while significantly high amounts of lycopene were detected in the tomatoes. The cholinesterase-inhibition and antioxidant properties of the “tomatoes” could make them good dietary means for the management of neurodegenerative disorders.

  14. Chemical Composition of Volatiles; Antimicrobial, Antioxidant and Cholinesterase Inhibitory Activity of Chaerophyllum aromaticum L. (Apiaceae) Essential Oils and Extracts.

    PubMed

    Petrović, Goran M; Stamenković, Jelena G; Kostevski, Ivana R; Stojanović, Gordana S; Mitić, Violeta D; Zlatković, Bojan K

    2017-05-01

    The present study reports the chemical composition of the headspace volatiles (HS) and essential oils obtained from fresh Chaerophyllum aromaticum root and aerial parts in full vegetative phase, as well as biological activities of their essential oils and MeOH extracts. In HS samples, the most dominant components were monoterpene hydrocarbons. On the other hand, the essential oils consisted mainly of sesquiterpenoids, representing 73.4% of the root and 63.4% of the aerial parts essential oil. The results of antibacterial assay showed that the aerial parts essential oil and MeOH extract have no antibacterial activity, while the root essential oil and extract showed some activity. Both of the tested essential oils exhibited anticholinesterase activity (47.65% and 50.88%, respectively); MeOH extract of the root showed only 8.40% inhibition, while aerial part extract acted as an activator of cholinesterase. Regarding the antioxidant activity, extracts were found to be more effective than the essential oils. © 2017 Wiley-VHCA AG, Zurich, Switzerland.

  15. The measurement of cholinesterase activities as a biomarker in chub (Leuciscus cephalus): the fish length should not be ignored.

    PubMed

    Flammarion, P; Noury, P; Garric, J

    2002-01-01

    Biomarkers are early warning systems of the exposure of aquatic organisms to pollutants. Among them, the measurement of the cholinesterase (ChE) activities in fish muscle is a biomarker of the exposure to organophosphosphates and carbamates pesticides. As such it has been used in numerous field studies both in marine and continental waters. Cyprinids (chub, Leuciscus cephalus) were sampled in river sites (France) in relatively clean and polluted areas. We performed the statistical analysis of the ChE activities and we generally observed a statistical relationship between ChE activities and fish length, the larger fish having the lower ChE activities. We concluded that the great majority of the significant differences in ChE activities between sites could be due in fact to differences in fish length between field samples. We stress the importance of taking into account the fish length whenever differences in ChE levels between field sites must be interpreted.

  16. New antimuscarinic agents for improved treatment of poisoning by cholinesterase inhibitors. Annual report, 1 November 1983-1 August 1984

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Stubbins, J.F.

    The object of this project is to find a more effective antimuscarinic agent than atropine for use as an antidote for poisoning by organophosphate cholinesterase inhibitors. To start this search, 30 structurally diverse antimuscarinic agents have been selected for initial testing. These compounds are to be evaluated for peripheral and central antimuscarinic activity in a variety of in vitro and in vivo tests in addition to determining their effectiveness as antidotes (in combination with an oxime reactivator) for poisoning by soman. Twenty-two of the compounds have now been evaluated for their ability to block acetylcholine-induced contractions in guinea pig intestinalmore » smooth muscle when compared to atropine. Ability to displace radiolabeled quinuclidinyl benzilate from muscarinic receptors of mouse brain homogenate has been determined for atropine, hyoscine and 26 of the compounds. Only triflupromazine appeared to have a distinctly greater affinity for brain receptors than muscle receptors to atropine. Intestinal smooth muscle blockade; oxotremorine tremor inhibition; muscarinic receptor subtypes.« less

  17. Disease-modifying anti-Alzheimer's drugs: inhibitors of human cholinesterases interfering with β-amyloid aggregation.

    PubMed

    Brogi, Simone; Butini, Stefania; Maramai, Samuele; Colombo, Raffaella; Verga, Laura; Lanni, Cristina; De Lorenzi, Ersilia; Lamponi, Stefania; Andreassi, Marco; Bartolini, Manuela; Andrisano, Vincenza; Novellino, Ettore; Campiani, Giuseppe; Brindisi, Margherita; Gemma, Sandra

    2014-07-01

    We recently described multifunctional tools (2a-c) as potent inhibitors of human Cholinesterases (ChEs) also able to modulate events correlated with Aβ aggregation. We herein propose a thorough biological and computational analysis aiming at understanding their mechanism of action at the molecular level. We determined the inhibitory potency of 2a-c on Aβ1-42 self-aggregation, the interference of 2a with the toxic Aβ oligomeric species and with the postaggregation states by capillary electrophoresis analysis and transmission electron microscopy. The modulation of Aβ toxicity was assessed for 2a and 2b on human neuroblastoma cells. The key interactions of 2a with Aβ and with the Aβ-preformed fibrils were computationally analyzed. 2a-c toxicity profile was also assessed (human hepatocytes and mouse fibroblasts). Our prototypical pluripotent analogue 2a interferes with Aβ oligomerization process thus reducing Aβ oligomers-mediated toxicity in human neuroblastoma cells. 2a also disrupts preformed fibrils. Computational studies highlighted the bases governing the diversified activities of 2a. Converging analytical, biological, and in silico data explained the mechanism of action of 2a on Aβ1-42 oligomers formation and against Aβ-preformed fibrils. This evidence, combined with toxicity data, will orient the future design of safer analogues. © 2014 John Wiley & Sons Ltd.

  18. Effects of cholinesterase inhibitors on rat nicotinic receptor levels in vivo and in vitro

    PubMed Central

    Sabbagh, Marwan N.

    2010-01-01

    Cholinesterase inhibitors (ChEIs) are the mainstay of treatment for AD but differ by secondary mechanisms of action. We determine the effects of sub-chronic dosing of ChEIs on α7 and non-α7 nAChRs and determine if differences can be observed between them. Sprague–Dawley rats were administered donepezil, galantamine; rivastigmine at two doses each, in saline SQ twice daily or with nicotine (0.4 mg/kg) as a positive control. After 14 days the animals were sacrificed, and the levels of nAChRs were measured using [3H]-EPI to measure non-α7 nAChRs and [3H]-MLA to measure α7 nAChRs. In the cortex, all compounds tested at the higher doses significantly increased the levels of both [3H]-EPI and [3H]-MLA. In the hippocampus all compounds significantly increased [3H]-EPI but had no effect on [3H]-MLA binding. No effects were observed in the striatum with treatment. There were no differences observed among the ChEIs. In cell cultures, none of the ChEIs increased non-α7 or α7 receptor binding. Treatment with ChEIs result in similar increases in receptor levels which suggest that the increases in nAChRs may be due simply to the increases in synaptic levels of acetylcholine. PMID:18726544

  19. Processing of Cholinesterase-like α/β-Hydrolase Fold Proteins: Alterations Associated with Congenital Disorders

    PubMed Central

    De Jaco, Antonella; Comoletti, Davide; Dubi, Noga; Camp, Shelley; Taylor, Palmer

    2016-01-01

    The α/β hydrolase fold family is perhaps the largest group of proteins presenting significant structural homology with divergent functions, ranging from catalytic hydrolysis to heterophilic cell adhesive interactions to chaperones in hormone production. All the proteins of the family share a common three-dimensional core structure containing the α/β-hydrolase fold domain that is crucial for proper protein function. Several mutations associated with congenital diseases or disorders have been reported in conserved residues within the α/β-hydrolase fold domain of cholinesterase-like proteins, neuroligins, butyrylcholinesterase and thyroglobulin. These mutations are known to disrupt the architecture of the common structural domain either globally or locally. Characterization of the natural mutations affecting the α/β-hydrolase fold domain in these proteins has shown that they mainly impair processing and trafficking along the secretory pathway causing retention of the mutant protein in the endoplasmic reticulum. Studying the processing of α/β-hydrolase fold mutant proteins should uncover new functions for this domain, that in some cases require structural integrity for both export of the protein from the ER and for facilitating subunit dimerization. A comparative study of homologous mutations in proteins that are closely related family members, along with the definition of new three-dimensional crystal structures, will identify critical residues for the assembly of the α/β-hydrolase fold. PMID:21933121

  20. Synthesis and biological evaluation of a new series of ebselen derivatives as glutathione peroxidase (GPx) mimics and cholinesterase inhibitors against Alzheimer's disease.

    PubMed

    Luo, Zonghua; Liang, Liang; Sheng, Jianfei; Pang, Yanqing; Li, Jianheng; Huang, Ling; Li, Xingshu

    2014-02-15

    A series of ebselen derivatives were designed, synthesised and evaluated as inhibitors of cholinesterases (ChEs) and glutathione peroxidase (GPx) mimics. Most of the compounds were found to be potent against AChEs and BuChE, compounds 5e and 5i, proved to be the most potent against AChE with IC₅₀ values of 0.76 and 0.46 μM, respectively. Among these hybrids, most of the compounds were found to be good GPx mimics compare with ebselen. The selected compounds 5e and 5i were also used to determine the catalytic parameters and in vitro hydrogen peroxide scavenging activity. The results indicate that compounds 5e and 5i may be excellent multifunctional agents for the treatment of AD. Copyright © 2014 Elsevier Ltd. All rights reserved.

  1. O-Hydroxyl- or o-amino benzylamine-tacrine hybrids: multifunctional biometals chelators, antioxidants, and inhibitors of cholinesterase activity and amyloid-β aggregation.

    PubMed

    Mao, Fei; Huang, Ling; Luo, Zonghua; Liu, Anqiu; Lu, Chuanjun; Xie, Zhiyong; Li, Xingshu

    2012-10-01

    In an effort to identify novel multifunctional drug candidates for the treatment of Alzheimer's disease (AD), a series of hybrid molecules were synthesised by reacting N-(aminoalkyl)tacrine with salicylic aldehyde or derivatives of 2-aminobenzaldehyde. These compounds were then evaluated as multifunctional anti-Alzheimer's disease agents. All of the hybrids are potential biometal chelators, and in addition, most of them were better antioxidants and inhibitors of cholinesterases and amyloid-β (Aβ) aggregation than the lead compound tacrine. Compound 7c has the potential to be a candidate for AD therapy: it is a much better inhibitor of acetylcholinesterase (AChE) than tacrine (IC(50): 0.55 nM vs 109 nM), has good biometal chelation ability, is able to inhibit Aβ aggregation and has moderate antioxidant activity (1.22 Trolox equivalents). Copyright © 2012 Elsevier Ltd. All rights reserved.

  2. Dual functional cholinesterase and MAO inhibitors for the treatment of Alzheimer's disease: synthesis, pharmacological analysis and molecular modeling of homoisoflavonoid derivatives.

    PubMed

    Wang, Yali; Sun, Yang; Guo, Yueyan; Wang, Zechen; Huang, Ling; Li, Xingshu

    2016-01-01

    Because of the complexity of Alzheimer's disease (AD), the multi-target-directed ligand (MTDL) strategy is expected to provide superior effects for the treatment of AD, instead of the classic one-drug-one-target strategy. In this context, we focused on the design, synthesis and evaluation of homoisoflavonoid derivatives as dual acetyl cholinesterase (AChE) and monoamine oxidase (MAO-B) inhibitors. Among all the synthesized compounds, compound 10 provided a desired balance of AChE and hMAO-B inhibition activities, with IC50 value of 3.94 and 3.44 μM, respectively. Further studies revealed that compound 10 was a mixed-type inhibitor of AChE and an irreversible inhibitor of hMAO-B, which was also confirmed by molecular modeling studies. Taken together, the data indicated that 10 was a promising dual functional agent for the treatment of AD.

  3. Cholinesterase inhibitory activities of Apai-sa-le recipe and its ingredients.

    PubMed

    Senavong, Pimolvan; Sattaponpan, Chitsanucha; Silavat Suk-um; Itharat, Arunporn

    2014-08-01

    Acetylcholinesterase and butyrylcholoinesterase inhibitors are well-known drugs commonly used in the treatment ofAlzheimer's disease (AD) to improve cognitive function. These enzyme inhibitors were reported to be found in manyplants. Apai-sa-le recipe was a Thai tradition used as nootropic recipe and formerly claimed to improve memory. Therefore, it is interesting to investigate cholinesterase inhibitory activity ofthe recipe and its ingredients. To determine the whole recipe ofApai-sa-le and its ingredients for inhibitory effect on acetylcholinesterase (AChE) and human butyrylcholinesterase (BuChE) activities. Thirty grams of each plant and 181 grams of the whole recipe were separately extracted by 95% ethanol, after filtered the filtrate were evaporated and vacuum-dried at 45°C. By Elman method, the inhibitory activities of both enzymes were assessed. The volatile constituents ofeach extract were determined by GCMS. The constituents in the non- volatile extract were examined by TLC and the antioxidant activity was determined. Four plants exhibited specific BuChE inhibitor were Lepidium sativum Linn. (Ls), Piper nigrum L. (Pn), Angelica dahurica Benth (Ad) andAtractylodes lancea DC. (Al), which shown the lC50 of 5.59, 24.52, 73.23, 96.25 μg/ml, respectively whereas galantamine and the whole recipe showed IC50 of 0.59 and 236 μg/ml. Only Pn extract inhibited AChE at lCso of 25.46 μg/ml. By GCMS and TLC fingerprints revealed the main constituents in LS, Ad, Al andPn as apiol, cumialdehyde, furanodiene and piperine. Moreover nine plant extracts and the whole recipe showed antioxidant activity. Lepidium sativum Linn. (Ls) extract showed the most potency on BuChE inhibitory effect. Three ingredients and the whole recipe exhibited mild activity. Only Piper nigrum L demonstrated inhibition effect on both AChE and BuChE.

  4. [Treatment pattern of Alzheimer's disease with cholinesterase inhibitors (TRAIN study)].

    PubMed

    Gil-Néciga, E; Gobartt, A L

    To describe the relation between the level of cognitive impairment in Alzheimer's disease and the use of cholinesterase inhibitors (ChEIs) in neurology, geriatric and psychiatric units, and to establish the clinical profile of these patients. An epidemiological, multi-centre, cross-sectional study was conducted. Subjects included in the study were consecutive outpatients diagnosed with Alzheimer's disease, in accordance with the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders, and who had been treated with rivastigmine, donepezil or galantamine, either on its own or in association with memantine in the last six months. The recruitment period lasted three months. In a single visit, researchers determined the medication that was used, the dose, the mini-mental test, the overall clinical impression-overall improvement and the overall clinical impression-severity of the disease. A total of 1940 patients were selected from neurology, psychiatric and geriatric services all over the country. Possible differences in the habits of different specialists as regards prescribing were analysed, together with the relation between cognitive impairment and the type of medication employed. The mean age of the patients was 77 +/- 6.6 years, 62% of whom were females; the mean score on the mini-mental test was 17.4 +/- 5.5. The mini-mental score was similar in patients treated with rivastigmine (18.02 +/- 5.23), donepezil (17.08 +/- 5.54) or galantamine (17.34 +/- 5.38). In patients who were treated with memantine in association with a ChEI, the mini-mental score was significantly lower (11.44 +/- 5.68) (p < 0.0001). The doses of the different ChEIs used by the specialists were similar. A higher percentage of patients had maximum doses of donepezil (81%) than in the cases of rivastigmine (43%) and galantamine (67%). The different specialists involved (neurologists, geriatricians and psychiatrists) displayed similar habits regarding the utilisation of Ch

  5. Hydroxybenzoic Acid Derivatives as Dual-Target Ligands: Mitochondriotropic Antioxidants and Cholinesterase Inhibitors.

    PubMed

    Oliveira, Catarina; Cagide, Fernando; Teixeira, José; Amorim, Ricardo; Sequeira, Lisa; Mesiti, Francesco; Silva, Tiago; Garrido, Jorge; Remião, Fernando; Vilar, Santiago; Uriarte, Eugenio; Oliveira, Paulo J; Borges, Fernanda

    2018-01-01

    Alzheimer's disease (AD) is a multifactorial age-related disease associated with oxidative stress (OS) and impaired cholinergic transmission. Accordingly, targeting mitochondrial OS and restoring cholinergic transmission can be an effective therapeutic strategy toward AD. Herein, we report for the first time dual-target hydroxybenzoic acid (HBAc) derivatives acting as mitochondriotropic antioxidants and cholinesterase (ChE) inhibitors. The studies were performed with two mitochondriotropic antioxidants AntiOxBEN 1 (catechol derivative), and AntiOxBEN 2 (pyrogallol derivative) and compounds 15-18 , which have longer spacers. Compounds AntiOxBEN 1 and 15 , with a shorter carbon chain spacer (six- and eight-carbon) were shown to be potent antioxidants and BChE inhibitors (IC 50 = 85 ± 5 and 106 ± 5 nM, respectively), while compounds 17 and 18 with a 10-carbon chain were more effective AChE inhibitors (IC 50 = 7.7 ± 0.4 and 7.2 ± 0.5 μM, respectively). Interestingly, molecular modeling data pointed toward bifunctional ChEs inhibitors. The most promising ChE inhibitors acted by a non-competitive mechanism. In general, with exception of compounds 15 and 17 , no cytotoxic effects were observed in differentiated human neuroblastoma (SH-SY5Y) and human hepatocarcinoma (HepG2) cells, while Aβ-induced cytotoxicity was significantly prevented by the new dual-target HBAc derivatives. Overall, due to its BChE selectivity, favorable toxicological profile, neuroprotective activity and drug-like properties, which suggested blood-brain barrier (BBB) permeability, the mitochondriotropic antioxidant AntiOxBEN 1 is considered a valid lead candidate for the development of dual acting drugs for AD and other mitochondrial OS-related diseases.

  6. Hydroxybenzoic Acid Derivatives as Dual-Target Ligands: Mitochondriotropic Antioxidants and Cholinesterase Inhibitors

    PubMed Central

    Oliveira, Catarina; Cagide, Fernando; Teixeira, José; Amorim, Ricardo; Sequeira, Lisa; Mesiti, Francesco; Silva, Tiago; Garrido, Jorge; Remião, Fernando; Vilar, Santiago; Uriarte, Eugenio; Oliveira, Paulo J.; Borges, Fernanda

    2018-01-01

    Alzheimer's disease (AD) is a multifactorial age-related disease associated with oxidative stress (OS) and impaired cholinergic transmission. Accordingly, targeting mitochondrial OS and restoring cholinergic transmission can be an effective therapeutic strategy toward AD. Herein, we report for the first time dual-target hydroxybenzoic acid (HBAc) derivatives acting as mitochondriotropic antioxidants and cholinesterase (ChE) inhibitors. The studies were performed with two mitochondriotropic antioxidants AntiOxBEN1 (catechol derivative), and AntiOxBEN2 (pyrogallol derivative) and compounds 15–18, which have longer spacers. Compounds AntiOxBEN1 and 15, with a shorter carbon chain spacer (six- and eight-carbon) were shown to be potent antioxidants and BChE inhibitors (IC50 = 85 ± 5 and 106 ± 5 nM, respectively), while compounds 17 and 18 with a 10-carbon chain were more effective AChE inhibitors (IC50 = 7.7 ± 0.4 and 7.2 ± 0.5 μM, respectively). Interestingly, molecular modeling data pointed toward bifunctional ChEs inhibitors. The most promising ChE inhibitors acted by a non-competitive mechanism. In general, with exception of compounds 15 and 17, no cytotoxic effects were observed in differentiated human neuroblastoma (SH-SY5Y) and human hepatocarcinoma (HepG2) cells, while Aβ-induced cytotoxicity was significantly prevented by the new dual-target HBAc derivatives. Overall, due to its BChE selectivity, favorable toxicological profile, neuroprotective activity and drug-like properties, which suggested blood-brain barrier (BBB) permeability, the mitochondriotropic antioxidant AntiOxBEN1 is considered a valid lead candidate for the development of dual acting drugs for AD and other mitochondrial OS-related diseases. PMID:29740575

  7. Hydroxybenzoic acid derivatives as dual-target ligands: mitochondriotropic antioxidants and cholinesterase inhibitors

    NASA Astrophysics Data System (ADS)

    Oliveira, Catarina; Cagide, Fernando; Teixeira, José; Amorim, Ricardo; Sequeira, Lisa; Mesiti, Francesco; Silva, Tiago; Garrido, Jorge; Remião, Fernando; Vilar, Santiago; Uriarte, Eugenio; Oliveira, Paulo J.; Borges, Fernanda

    2018-04-01

    Alzheimer’s disease (AD) is a multifactorial age-related disease associated with oxidative stress (OS) and impaired cholinergic transmission. Accordingly, targeting mitochondrial OS and restoring cholinergic transmission can be an effective therapeutic strategy towards AD. Herein, we report for the first time dual-target hydroxybenzoic acid (HBAc) derivatives acting as mitochondriotropic antioxidants and cholinesterase (ChE) inhibitors. The studies were performed with two mitochondriotropic antioxidants AntiOxBEN1 (catechol derivative), and AntiOxBEN2 (pyrogallol derivative) and compounds 15-18, which have longer spacers. Compounds AntiOxBEN1 and 15, with a shorter carbon chain spacer (six- and eight-carbon) were shown to be potent antioxidants and BChE inhibitors (IC50 = 85 ± 5 and 106 ± 5 nM, respectively), while compounds 17 and 18 with a ten-carbon chain were more effective AChE inhibitors (IC50 = 7.7 ± 0.4 and 7.2 ± 0.5 nM, respectively). Interestingly, molecular modelling data pointed towards bifunctional ChEs inhibitors. The most promising ChE inhibitors acted by a non-competitive mechanism. In general, with exception of compounds 15 and 17, no cytotoxic effects were observed in differentiated human neuroblastoma (SH-SY5Y) and human hepatocarcinoma (HepG2) cells, while Αβ-induced cytotoxicity was significantly prevented by the new dual-target HBAc derivatives. Overall, due to its BChE selectivity, favourable toxicological profile, neuroprotective activity and drug-like properties, which suggested blood-brain barrier (BBB) permeability, the mitochondriotropic antioxidant AntiOxBEN1 is considered a valid lead candidate for the development of dual acting drugs for AD and other mitochondrial OS-related disease

  8. Cholinesterase assay for monitoring the kinetics of the JD6. 5 organophosphorus acid anhydrase in detoxification of diisopropylfluorophosphate. Final report, January-June 1988

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Yeh, H.R.; Cheng, T.C.; DeFrank, J.J.

    1992-06-01

    In the present studies, cholinesterase was used for monitoring the enzymatic activities of the JD6.5 organophosphorus acid anhydrase. The kinetic data indicated that: (1) the first order of kinetic constants (k) and Vmax values of the enzymatic reactions increased as the concentrations of the enzyme increased; (2) while the half-life (tl/2) of diisopropylfluorophosphate (DFP) hydrolysis decreased as the enzyme concentrations increased; (3) the minimum time required for hydrolysis of 9mM of DFP was 3 min at the concentrations of the enzyme present; Km values of DFP were found to be in range of 5mM; and (4) both MnCl2 and NaClmore » were found to be required for the optimal activity of the enzyme.« less

  9. Novel multipotent phenylthiazole-tacrine hybrids for the inhibition of cholinesterase activity, β-amyloid aggregation and Ca²⁺ overload.

    PubMed

    Wang, Yue; Wang, Fang; Yu, Jun-Ping; Jiang, Feng-Chao; Guan, Xin-Lei; Wang, Can-Ming; Li, Lei; Cao, Hui; Li, Ming-Xing; Chen, Jian-Guo

    2012-11-01

    In this study, a series of multipotent phenylthiazole-tacrine hybrids (7a-7e, 8, and 9a-9m) were synthesized and biologically evaluated. Screening results showed that phenylthiazole-tacrine hybrids were potent cholinesterase inhibitors with pIC(50) (-logIC(50)) value ranging from 5.78 ± 0.05 to 7.14 ± 0.01 for acetylcholinesterase (AChE), and from 5.75 ± 0.03 to 10.35 ± 0.15 for butyrylcholinesterase (BuChE). The second series of phenylthiazole-tacrine hybrids (9a-9m) could efficiently prevent Aβ(1-42) self-aggregation. The structure-activity relationship revealed that their inhibitory potency relied on the type of middle linker and substitutions at 4'-position of 4-phenyl-2-aminothiazole. In addition, 7a and 7c also displayed the Ca(2+) overload blockade effect in the primary cultured cortical neurons. Consequently, these compounds emerged as promising molecules for the therapy of Alzheimer's disease. Copyright © 2012 Elsevier Ltd. All rights reserved.

  10. Isoindoline-1,3-dione derivatives targeting cholinesterases: design, synthesis and biological evaluation of potential anti-Alzheimer's agents.

    PubMed

    Guzior, Natalia; Bajda, Marek; Rakoczy, Jurand; Brus, Boris; Gobec, Stanislav; Malawska, Barbara

    2015-04-01

    Alzheimer's disease is a fatal neurodegenerative disorder with a complex etiology. Because the available therapy brings limited benefits, the effective treatment for Alzheimer's disease remains the unmet challenge. Our aim was to develop a new series of donepezil-based compounds endowed with inhibitory properties against cholinesterases and β-amyloid aggregation. We designed the target compounds as dual binding site acetylcholinesterase inhibitors with N-benzylamine moiety interacting with the catalytic site of the enzyme and an isoindoline-1,3-dione fragment interacting with the peripheral anionic site of the enzyme. The results of pharmacological evaluation lead us to identify a compound 3b as the most potent and selective human acetylcholinesterase inhibitor (hAChE IC50=0.361μM). Kinetic studies revealed that 3b inhibited acetylcholinesterase in non-competitive mode. The result of the parallel artificial membrane permeability assay for the blood-brain barrier indicated that the compound 3b would be able to cross the blood-brain barrier and reach its biological targets in the central nervous system. The selected compound 3b represents a potential lead structure for further development of anti-Alzheimer's agents. Copyright © 2015 Elsevier Ltd. All rights reserved.

  11. ELECTRON MICROSCOPIC LOCALIZATION OF ACETYLCHOLINESTERASE AND NONSPECIFIC CHOLINESTERASE AT THE NEUROMUSCULAR JUNCTION BY THE GOLD-THIOCHOLINE AND GOLD-THIOLACETIC ACID METHODS

    PubMed Central

    Davis, Richard; Koelle, George B.

    1967-01-01

    By means of the gold-thiocholine (AuThCh) and gold-thiolacetic acid (AuThAc) methods, it has been demonstrated electron microscopically that acetylcholinesterase (AChE) is located at the prejunctional axoplasmic membrane and the postjunctional sarcoplasmic membrane, including the full lengths of its invaginations, at the motor end plate of mouse intercostal muscle. Nonspecific cholinesterase (ChE) is present in relatively low concentrations at the same sites, and in greater concentrations in the teloglial Schwann sheath cells. Significant amounts of reaction product appeared in the junctional cleft only after prolonged incubation with both methods. The identification of AChE and ChE was confirmed by the use of appropriate concentrations of several selective inhibitors. In confirmation of previous studies by light microscopy, the AuThCh method is more specific for AChE and ChE, whereas the AuThAc method allows greater accuracy of localization. PMID:6033530

  12. Inhibition on cholinesterase and tyrosinase by alkaloids and phenolics from Aristotelia chilensis leaves.

    PubMed

    Cespedes, Carlos L; Balbontin, Cristian; Avila, Jose G; Dominguez, Mariana; Alarcon, Julio; Paz, Cristian; Burgos, Viviana; Ortiz, Leandro; Peñaloza-Castro, Ignacio; Seigler, David S; Kubo, Isao

    2017-11-01

    It is reported in this study the effect of isolates from leaves of Aristotelia chilensis as inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and tyrosinase enzymes. The aim of the paper was to evaluate the activity of A. chilensis towards different enzymes. In addition to pure compounds, extracts rich in alkaloids and phenolics were tested. The most active F5 inhibited AChE (79.5% and 89.8% at 10.0 and 20.0 μg/mL) and against BChE (89.5% and 97.8% at 10.0 and 20.0 μg/mL), showing a strong mixed-type inhibition against AChE and BChE. F3 (a mixture of flavonoids and phenolics acids), showed IC 50 of 90.7 and 59.6 μg/mL of inhibitory activity against AChE and BChE, inhibiting the acetylcholinesterase competitively. Additionally, F3 showed and high potency as tyrosinase inhibitor with IC 50 at 8.4 μg/mL. Sample F4 (anthocyanidins and phenolic composition) presented a complex, mixed-type inhibition of tyrosinase with a IC 50 of 39.8 μg/mL. The findings in this investigation show that this natural resource has a strong potential for future research in the search of new phytotherapeutic treatments for cholinergic deterioration ailments avoiding the side effects of synthetic drugs. This is the first report as cholinesterases and tyrosinase inhibitors of alkaloids and phenolics from A. chilensis leaves. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. Behavioral dysfunctions correlate to altered physiology in rainbow trout (Oncorynchus mykiss) exposed to cholinesterase-inhibiting chemicals

    USGS Publications Warehouse

    Brewer, S.K.; Little, E.E.; DeLonay, A.J.; Beauvais, S.L.; Jones, S.B.; Ellersieck, Mark R.

    2001-01-01

    We selected four metrics of swimming behavior (distance swam, speed, rate of turning, and tortuosity of path) and the commonly used biochemical marker, brain cholinesterase (ChE) activity, to assess (1) the sensitivity and reliability of behavior as a potential biomarker in monitoring work, (2) the potential for these endpoints to be used in automated monitoring, and (3) the linkage between behavior and its underlying biochemistry. Malathion-exposed fish exhibited large decreases in distance and speed and swam in a more linear path than control fish after 24 h exposure. By 96 h exposure, fish still swam slower and traveled less distance; fish fully recovered after 48 h in clean water. Diazinon-exposed fish exhibited decreases in distance, speed, and turning rate compared to controls. After 48 h recovery in clean water, fish exposed to diazinon had not recovered to control levels. The behavioral responses provided measures of neurotoxicity that were easily quantifiable by automated means, implying that the inclusion of behavior in monitoring programs can be successful. Furthermore, correlations between behavior and biochemical endpoints, such as ChE inhibition, suggest that this approach can provide a meaningful link between biochemistry and behavior and can provide useful information on toxicant impacts.

  14. Behavioral dysfunctions correlate to altered physiology in rainbow trout (Oncorynchus mykiss) exposed to cholinesterase-inhibiting chemicals.

    PubMed

    Brewer, S K; Little, E E; DeLonay, A J; Beauvais, S L; Jones, S B; Ellersieck, M R

    2001-01-01

    We selected four metrics of swimming behavior (distance swam, speed, rate of turning, and tortuosity of path) and the commonly used biochemical marker, brain cholinesterase (ChE) activity, to assess (1) the sensitivity and reliability of behavior as a potential biomarker in monitoring work, (2) the potential for these endpoints to be used in automated monitoring, and (3) the linkage between behavior and its underlying biochemistry. Malathion-exposed fish exhibited large decreases in distance and speed and swam in a more linear path than control fish after 24 h exposure. By 96 h exposure, fish still swam slower and traveled less distance; fish fully recovered after 48 h in clean water. Diazinon-exposed fish exhibited decreases in distance, speed, and turning rate compared to controls. After 48 h recovery in clean water, fish exposed to diazinon had not recovered to control levels. The behavioral responses provided measures of neurotoxicity that were easily quantifiable by automated means, implying that the inclusion of behavior in monitoring programs can be successful. Furthermore, correlations between behavior and biochemical endpoints, such as ChE inhibition, suggest that this approach can provide a meaningful link between biochemistry and behavior and can provide useful information on toxicant impacts.

  15. Bird predation on cutworms (Lepidoptera: Noctuidae) in wheat fields and chlorpyrifos effects on brain cholinesterase activity

    USGS Publications Warehouse

    McEwen, L.C.; DeWeese, L.R.; Schladweiler, P.

    1986-01-01

    Horned larks, Eremophila alpestris (L.), and McCown's longspurs, Calcarius mccownii (Lawrence), were collected at intervals from two winter wheat fields in Montana [USA] after aerial application of chlorpyrifos to control cutworms. Both bird species had a high (95-100%) incidence of Lepidoptera, mostly pale western cutworms, Agrotis orthogonia Morrison, in their stomachs at 3 days postspray. Incidence of cutworms and other insects in stomachs of birds from sprayed fields was lower at 9 and 16 days postspray than in control birds, presumably due to insecticide-caused reduction of insects. Effects of birds on population dynamics of insect pests in wheat are unknown, but birds do contribute to cutworm mortality. Predation is one of the limiting factors to cutworm increase and can supplement insecticidal control. Brain cholinesterase activity in horned larks collected from the sprayed fields at 3 and 9 days postspray was significantly lower than in unexposed larks, but at 16 days the difference was not significant. Although nontarget birds clearly were exposed to chlorpyrifos and manifested a sublethal physiological response, toxic effects were less severe than those resulting from endrin application for cutworm control in wheat. More study is needed of larger chlorpyrifos-treated fields under a variety of conditions to fully assess effects on nontarget life.

  16. Determination of esterase activity and characterization of cholinesterases in the reef fish Haemulon plumieri.

    PubMed

    Leticia, Alpuche-Gual; Gerardo, Gold-Bouchot

    2008-11-01

    White grunt (Haemulon plumieri) has been proposed by the Mesoamerican Barrier Reef System (MBRS) Synoptic Monitoring Program as a bioindicator species. It is in this sense that the present study has a main goal to evaluate this organism's suitability as an indicator species. Individuals were captured during three seasons at the port of Sisal, Yucatan, Mexico which is located in an area that is considered to be weakly impacted by human activities such as agriculture or industry. Both cholinesterase (ChE) and carboxylesterase (CbE) activities were measured in brain, muscle, liver and eye of sampled individuals. Results indicated that ChE and CbE activities were greatest in the brain (256.3 ± 43) and in the liver (191 ± 21), respectively. Furthermore, ChEs detected in brain, liver and muscle were characterized, and results suggested that the acetylcholinesterase (AChE) type was more abundant relative to pseudocholinesterase (BChE) which was rare. In addition, K(m) and V(max) and IC(50) values were calculated from the Michaelis-Menten equation. Finally, an additional experiment in vitro showed a significant decrease in both ChE and CbE activities when different tissues were exposed to model xenobiotics, such as benzo[a]pyrene and Chlorpyrifos. In conclusion, findings from this study confirm the potential suitability of H. plumieri as an organic pollution bioindicator species, and thus of practical use for environmental biomonitoring purposes.

  17. Distigmine Bromide Produces Sustained Potentiation of Guinea-Pig Urinary Bladder Motility by Inhibiting Cholinesterase Activity.

    PubMed

    Obara, Keisuke; Chino, Daisuke; Tanaka, Yoshio

    2017-01-01

    Distigmine is a cholinesterase (ChE) inhibitor used for the treatment of detrusor underactivity in Japan. Distigmine's pharmacological effects are known to be long-lasting, but the duration of its effect on urinary bladder contractile function has not been fully elucidated. The present study aimed to determine these effects in relation to the plasma concentrations of distigmine and its inhibition of ChE activities in blood, plasma, and bladder tissue. Intravesical pressures were recorded in anesthetized guinea-pigs for 12 h after the intravenous administration of saline or distigmine (0.01-0.1 mg/kg). Plasma distigmine concentrations were measured by liquid chromatograph-tandem mass spectrometry (LC-MS/MS), while ChE activities were assayed using 5,5'-dithiobis(2-nitrobenzoic acid). Distigmine (0.1 mg/kg) significantly increased the maximum intravesical pressure at micturition reflex for 12 h post-administration. In contrast, plasma distigmine was only detectable for 6 h post-administration in these animals and a one-compartment model calculated an elimination half-life of 0.7 h. However, bladder and blood acetylcholinesterase activities were significantly inhibited for 12 h after distigmine administration, although plasma ChE activities were not affected. The pharmacodynamic effects of distigmine thus persisted after its elimination from the circulation, indicating that it may bind to bladder acetylcholinesterase, producing sustained enzyme inhibition and enhancement of bladder contractility.

  18. Synthesis, biological evaluation and docking studies of 2,3-dihydroquinazolin-4(1H)-one derivatives as inhibitors of cholinesterases.

    PubMed

    Sarfraz, Muhammad; Sultana, Nargis; Rashid, Umer; Akram, Muhammad Safwan; Sadiq, Abdul; Tariq, Muhammad Ilyas

    2017-02-01

    In search of potent inhibitors of cholinesterases, we have synthesized and evaluate a number of 2,3-dihydroquinazolin-4(1H)-one derivatives. The synthetic approach provided an efficient synthesis of the target molecules with excellent yield. All the tested compounds showed activity against both the enzymes in micromolar range. In many case, the inhibition of both enzymes are higher than or comparable to the standard drug galatamine. With the selectivity index of 2.3 for AChE, compound 5f can be considered as a potential lead compound with a feature of dual AChE/BChE inhibition with IC 50 =1.6±0.10μM (AChE) and 3.7±0.18μM (BChE). Binding modes of the synthesized compounds were explored by using GOLD (Genetic Optimization for Ligand Docking) suit v5.4.1. The computed binding modes of these compounds in the active site of AChE and BChE provide an insight into the mechanism of inhibition of these two enzyme. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Effects of novel tacrine-related cholinesterase inhibitors in the reversal of 3-quinuclidinyl benzilate-induced cognitive deficit in rats--Is there a potential for Alzheimer's disease treatment?

    PubMed

    Misik, Jan; Korabecny, Jan; Nepovimova, Eugenie; Kracmarova, Alzbeta; Kassa, Jiri

    2016-01-26

    Inhibitors of cholinesterase are important drugs for therapy of Alzheimer's disease and the search for new modifications is extensive, including dual inhibitors or multi-target hybrid compounds. The aim of the present study was a preliminary evaluation of pro-cognitive effects of newly-developed 7-MEOTA-donepezil like hybrids (compounds no. 1 and 2) and N-alkylated tacrine derivatives (compounds no. 3 and 4) using an animal model of pharmacologically-induced cognitive deficit. Male Wistar rats were subjected to tests of learning and memory in a water maze and step-through passive avoidance task. Cognitive impairment was induced by 3-quinuclidinyl benzilate (QNB, 2mgkg(-1)), administered intraperitoneally 1h before training sessions. Cholinesterase inhibitors were administered as a single therapeutic dose following the QNB at 30min at the following dose rates; 1 (25.6mgkg(-1)), 2 (12.3mgkg(-1)), 3 (5.7mgkg(-1)), 4 (5.2mgkg(-1)). The decrease in total path within the 10-swim session (water maze), the preference for target quadrant (water maze) and the entrance latency (passive avoidance) were taken as indicators of learning ability in rats. The effects of novel compounds were compared to that of standards tacrine (5.2mgkg(-1)) and donepezil (2.65mgkg(-1)). QNB significantly impaired spatial navigation as well as fear learning. Generally, the performance of rats was improved when treated with novel inhibitors and this effect reached efficiency of standard donepezil at selected doses. There was a significant improvement in the groups treated with compounds 2 and 3 in all behavioral tasks. The rest of the novel compounds succeed in the passive avoidance test. In summary, the potential of novel inhibitors (especially compounds 2 and 3) was proved and further detailed evaluation of these compounds as potential drugs for Alzheimer's disease treatment is proposed. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  20. Optimization of Cholinesterase-Based Catalytic Bioscavengers Against Organophosphorus Agents.

    PubMed

    Lushchekina, Sofya V; Schopfer, Lawrence M; Grigorenko, Bella L; Nemukhin, Alexander V; Varfolomeev, Sergei D; Lockridge, Oksana; Masson, Patrick

    2018-01-01

    Organophosphorus agents (OPs) are irreversible inhibitors of acetylcholinesterase (AChE). OP poisoning causes major cholinergic syndrome. Current medical counter-measures mitigate the acute effects but have limited action against OP-induced brain damage. Bioscavengers are appealing alternative therapeutic approach because they neutralize OPs in bloodstream before they reach physiological targets. First generation bioscavengers are stoichiometric bioscavengers. However, stoichiometric neutralization requires administration of huge doses of enzyme. Second generation bioscavengers are catalytic bioscavengers capable of detoxifying OPs with a turnover. High bimolecular rate constants ( k cat / K m > 10 6 M -1 min -1 ) are required, so that low enzyme doses can be administered. Cholinesterases (ChE) are attractive candidates because OPs are hemi-substrates. Moderate OP hydrolase (OPase) activity has been observed for certain natural ChEs and for G117H-based human BChE mutants made by site-directed mutagenesis. However, before mutated ChEs can become operational catalytic bioscavengers their dephosphylation rate constant must be increased by several orders of magnitude. New strategies for converting ChEs into fast OPase are based either on combinational approaches or on computer redesign of enzyme. The keystone for rational conversion of ChEs into OPases is to understand the reaction mechanisms with OPs. In the present work we propose that efficient OP hydrolysis can be achieved by re-designing the configuration of enzyme active center residues and by creating specific routes for attack of water molecules and proton transfer. Four directions for nucleophilic attack of water on phosphorus atom were defined. Changes must lead to a novel enzyme, wherein OP hydrolysis wins over competing aging reactions. Kinetic, crystallographic, and computational data have been accumulated that describe mechanisms of reactions involving ChEs. From these studies, it appears that introducing

  1. Synthesis, biological assessment and molecular modeling of new dihydroquinoline-3-carboxamides and dihydroquinoline-3-carbohydrazide derivatives as cholinesterase inhibitors, and Ca channel antagonists.

    PubMed

    Tomassoli, Isabelle; Ismaili, Lhassane; Pudlo, Marc; de Los Ríos, Cristóbal; Soriano, Elena; Colmena, Inés; Gandía, Luis; Rivas, Luis; Samadi, Abdelouahid; Marco-Contelles, José; Refouvelet, Bernard

    2011-01-01

    The synthesis, biological evaluation, and molecular modeling of new 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamides(4), 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbohydrazide (6), and some hexahydropyrimido[5,4-c]quinoline-2,5-diones (9) produced earlier by our laboratory, as AChE/BuChE inhibitors, is described. From these analyses compound 4c resulted equipotent regarding the inhibition of cholinesterases'; inhibitors 6k, 9a, 9b were selective for AChE, whereas product 4d proved selective for BuChE. Docking analysis has been carry out in order to identify the binding mode in the active site, and to explain the observed selectivities. Only compound 9a has been shown to decrease K(+)-induced calcium signals in bovine chromaffin cells. Copyright © 2010 Elsevier Masson SAS. All rights reserved.

  2. Design, synthesis and biological evaluation of multifunctional tacrine-curcumin hybrids as new cholinesterase inhibitors with metal ions-chelating and neuroprotective property.

    PubMed

    Liu, Zhikun; Fang, Lei; Zhang, Huan; Gou, Shaohua; Chen, Li

    2017-04-15

    Total sixteen tacrine-curcumin hybrid compounds were designed and synthesized for the purpose of searching for multifunctional anti-Alzheimer agents. In vitro studies showed that these hybrid compounds showed good cholinesterase inhibitory activity. Particularly, the potency of K 3-2 is even beyond tacrine. Some of the compounds exhibited different selectivity on acetylcholinesterase or butyrylcholinesterase due to the structural difference. Thus, the structure and activity relationship is summarized and further discussed based on molecular modeling studies. The ORAC and MTT assays indicated that the hybrid compounds possessed pronounced antioxidant activity and could effectively protect PC12 cells from the H 2 O 2 /Aβ42-induced toxicity. Moreover, the hybrid compounds also showed positive metal ions-chelating ability in vitro, suggesting a potential to halt ion-induced Aβ aggregation. All the obtained results demonstrated that the tacrine-curcumin hybrid compounds, in particular compound K 3-2 , can be considered as potential therapeutic agents for Alzheimer's disease. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. 7-Methoxytacrine-adamantylamine heterodimers as cholinesterase inhibitors in Alzheimer's disease treatment--synthesis, biological evaluation and molecular modeling studies.

    PubMed

    Spilovska, Katarina; Korabecny, Jan; Kral, Jan; Horova, Anna; Musilek, Kamil; Soukup, Ondrej; Drtinova, Lucie; Gazova, Zuzana; Siposova, Katarina; Kuca, Kamil

    2013-02-20

    A structural series of 7-MEOTA-adamantylamine thioureas was designed, synthesized and evaluated as inhibitors of human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE). The compounds were prepared based on the multi-target-directed ligand strategy with different linker lengths (n = 2-8) joining the well-known NMDA antagonist adamantine and the hAChE inhibitor 7-methoxytacrine (7-MEOTA). Based on in silico studies, these inhibitors proved dual binding site character capable of simultaneous interaction with the peripheral anionic site (PAS) of hAChE and the catalytic active site (CAS). Clearly, these structural derivatives exhibited very good inhibitory activity towards hBChE resulting in more selective inhibitors of this enzyme. The most potent cholinesterase inhibitor was found to be thiourea analogue 14 (with an IC₅₀ value of 0.47 µM for hAChE and an IC₅₀ value of 0.11 µM for hBChE, respectively). Molecule 14 is a suitable novel lead compound for further evaluation proving that the strategy of dual binding site inhibitors might be a promising direction for development of novel AD drugs.

  4. Cholinesterase and Paraoxonase (PON1) enzyme activities in Mexican-American Mothers and Children from an Agricultural Community

    PubMed Central

    Gonzalez, V.; Huen, K.; Venkat, S.; Pratt, K.; Xiang, P.; Harley, K.G.; Kogut, K.; Trujillo, C.M.; Bradman, A.; Eskenazi, B.; Holland, N.T.

    2014-01-01

    Exposure to organophosphate and carbamate pesticides can lead to neurotoxic effects through inhibition of cholinesterase enzymes. The paraoxonase (PON1) enzyme can detoxify oxon derivatives of some organophosphates. Lower PON1, acetylcholinesterase, and butyrylcholinesterase activities have been reported in newborns relative to adults, suggesting increased susceptibility to organophosphate exposure in young children. We determined PON1, acetylcholinesterase, and butyrylcholinesterase activities in Mexican-American mothers and their 9-year-old children (n=202 pairs) living in an agricultural community in California. We used paired t-tests to compare enzymatic activities among mothers and their children and analysis of variance to determine which factors are associated with enzyme activities. Substrate-specific PON1 activities were slightly lower in children than their mothers; however, these differences were not statistically significant. We observed significantly lower acetylcholinesterase but higher butyrylcholinesterase levels in children compared to their mothers. Mean butyrylcholinesterase levels were strongly associated with child obesity status (BMI Z scores >95%). We observed highly significant correlations among mother-child pairs for each of the enzymatic activities analyzed; however, PON1 activities did not correlate with acetylcholinesterase or butyrylcholinesterase activities. Our findings suggest that by age nine, PON1 activities approach adult levels and host factors including sex and obesity may affect key enzymes involved in pesticide metabolism. PMID:22760442

  5. A Statewide Evaluation of the California Medical Supervision Program Using Cholinesterase Electronic Laboratory Reporting Data

    PubMed Central

    Laribi, Ouahiba; Malig, Brian; Sutherland-Ashley, Katherine; Broadwin, Rachel; Wieland, Walker; Salocks, Charles

    2017-01-01

    The California Medical Supervision program is designed to protect workers who regularly mix, load, or apply the highly toxic Category I and II organophosphates and carbamates from overexposure by monitoring cholinesterase (ChE) inhibition in plasma and red blood cells. Since January 2011, testing laboratories are required to report test results electronically to the California Department of Pesticide Regulation who shares it with the Office of Environmental Health Hazard Assessment for evaluation. The purpose of this study is to assess the utility of this reporting in evaluating the effectiveness of the Program for illness surveillance and prevention. From 2011 to 2013, we received more than 90 000 test results. Despite data gaps and data quality issues, we were able to perform spatial and temporal analyses and developed a screening tool to identify individuals potentially at risk of overexposure. The data analysis provided some evidence that the Program is effective in protecting agricultural workers handling the most toxic ChE-inhibiting pesticides even though it also identified some areas of potential concerns with individuals that appeared lacking corrective actions in the workplace in response to excessive ChE depressions and parts of the state with disproportionately at-risk individuals. However, changes to the electronic reporting are needed to more accurately identify tests related to the Program and therefore improve the utility of the data received. Moreover, data analysis also revealed that electronic reporting has its limitation in evaluating the Program.

  6. Synthesis, Biological Evaluation and Molecular Docking Study of Hydrazone-Containing Pyridinium Salts as Cholinesterase Inhibitors.

    PubMed

    Parlar, Sulunay; Bayraktar, Gulsah; Tarikogullari, Ayse Hande; Alptüzün, Vildan; Erciyas, Ercin

    2016-01-01

    A series of pyridinium salts bearing alkylphenyl groups at 1 position and hydrazone structure at 4 position of the pyridinium ring were synthesized and evaluated for the inhibition of both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes. The cholinesterase (ChE) inhibitory activity studies were carried out by using the Ellman's colorimetric method. All compounds displayed considerable AChE and BuChE inhibitory activity and some of the compounds manifested remarkable anti-AChE activity compared to the reference compound, galantamine. Among the title compounds, the series including benzofuran aromatic ring exhibited the best inhibitory activity both on AChE and BuChE enzymes. Compound 3b, 4-[2-(1-(benzofuran-2-yl)ethylidene)hydrazinyl]-1-(3-phenylpropyl)pyridinium bromide, was the most active compound with IC50 value of 0.23 (0.24) µM against enantiomeric excess (ee)AChE (human (h)AChE) while compound 3a, 4-[2-(1-(benzofuran-2-yl)ethylidene)hydrazinyl]-1-phenethylpyridinium bromide, was the most active compound with IC50 value of 0.95 µM against BuChE. Moreover, 3a and b exhibited higher activity than the reference compound galantamine (eeAChE (hAChE) IC50 0.43 (0.52) µM; BuChE IC50 14.92 µM). Molecular docking studies were carried out on 3b having highest inhibitory activity against AChE.

  7. Toxicodynamic analysis of the combined cholinesterase inhibition by paraoxon and methamidophos in human whole blood

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Bosgra, Sieto; Eijkeren, Jan C.H. van; Schans, Marcel J. van der

    2009-04-01

    Theoretical work has shown that the isobole method is not generally valid as a method for testing the absence or presence of interaction (in the biochemical sense) between chemicals. The present study illustrates how interaction can be tested by fitting a toxicodynamic model to the results of a mixture experiment. The inhibition of cholinesterases (ChE) in human whole blood by various dose combinations of paraoxon and methamidophos was measured in vitro. A toxicodynamic model describing the processes related to both OPs in inhibiting AChE activity was developed, and fit to the observed activities. This model, not containing any interaction betweenmore » the two OPs, described the results from the mixture experiment well, and it was concluded that the OPs did not interact in the whole blood samples. While this approach of toxicodynamic modeling is the most appropriate method for predicting combined effects, it is not rapidly applicable. Therefore, we illustrate how toxicodynamic modeling can be used to explore under which conditions dose addition would give an acceptable approximation of the combined effects from various chemicals. In the specific case of paraoxon and methamidophos in whole blood samples, it was found that dose addition gave a reasonably accurate prediction of the combined effects, despite considerable difference in some of their rate constants, and mildly non-parallel dose-response curves. Other possibilities of validating dose-addition using toxicodynamic modeling are briefly discussed.« less

  8. Synthesis, biological activity and molecular modeling of 4-fluoro-N-[ω-(1,2,3,4-tetrahydroacridin-9-ylamino)-alkyl]-benzamide derivatives as cholinesterase inhibitors.

    PubMed

    Szymański, P; Markowicz, M; Bajda, M; Malawska, B; Mikiciuk-Olasik, E

    2012-12-01

    The aim of this study was to synthesize and determine the biological activity of new derivatives of 4-fluorobenzoic acid and tetrahydroacridine towards inhibition of cholinesterases. Compounds were synthesized in condensation reaction between 9-aminoalkyl-tetrahydroacridines and the activated 4-fluorobenzoic acid. Properties towards inhibition of acetyl- and butyrylcholinesterase were estimated according to Ellman's spectrophotometric method. Among synthesized compounds the most active were compounds 4a and 4d. These compounds, in comparison with tacrine, were characterized by the similar values of IC50. Among all obtained compounds, 4d presented the highest selectivity towards inhibition of acetylcholinesterase. Molecular modeling studies revealed that all derivatives presented similar extended conformation in the gorge of acetylcholinesterase, however, there were 2 main conformations in the active center of butyrylcholinesterase: bent and extended conformation. © Georg Thieme Verlag KG Stuttgart · New York.

  9. Oral administration of pyridostigmine bromide and huperzine A protects human whole blood cholinesterases from ex vivo exposure to soman.

    PubMed

    Gordon, Richard K; Haigh, Julian R; Garcia, Gregory E; Feaster, Shawn R; Riel, Michael A; Lenz, David E; Aisen, Paul S; Doctor, Bhupendra P

    2005-12-15

    Cholinesterases (ChEs) are classified as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) according to their substrate specificity and sensitivity to selected inhibitors. The activities of AChE in red blood cells (RBC-AChE) and BChE in serum can be used as potential biomarkers of suppressed and/or heightened activity in the central and peripheral nervous systems. Exposure to organophosphate (OP) chemical warfare agents (CWAs), pesticides, anesthetics, and a variety of drugs such as cocaine, as well as some neurodegenerative and liver disease states, selectively reduces AChE or BChE activity. In humans, the toxicity of pesticides is well documented. Therefore, blood cholinesterase activity can be exploited as a tool for confirming exposure to these agents and possible treatments. Current assays for measurement of RBC-AChE and serum BChE require several labor-intensive processing steps, suffer from wide statistical variation, and there is no inter-laboratory conversion between methods. These methods, which determine only the serum BChE or RBC-AChE but not both, include the Ellman, radiometric, and deltapH (modified Michel) methods. In contrast, the Walter Reed Army Institute of Research Whole Blood (WRAIR WB, US Patent #6,746,850) cholinesterase assay rapidly determines the activity of both AChE and BChE in unprocessed (uncentrifuged) whole blood, uses a minimally invasive blood sampling technique (e.g., blood from a finger prick), and is semi-automated for high-throughput using the Biomek 2000 robotic system. To date, the WRAIR whole blood assay was used to measure AChE and BChE activities in human blood from volunteers in FDA clinical trials. In the first FDA study, 24 human subjects were given either 30 mg PB orally (n = 19) or placebo (n = 5). Blood samples were obtained pre-dosing and 2.5, 5, 8, and 24 h post-dosing. The samples were analyzed for AChE and BChE activity using the WRAIR WB robotic system, and for PB concentration by HPLC. We found that

  10. Human serum cholinesterase from liver pathological samples exhibit highly elevated aryl acylamidase activity.

    PubMed

    Boopathy, Rathanam; Rajesh, Ramanna Valmiki; Darvesh, Sultan; Layer, Paul G

    2007-05-01

    Although aspartate aminotransferase (AST) and gamma-glutamyltransferase (gamma GT) enzymes are widely used as markers for liver disorders, the ubiquitous enzyme butyrylcholinesterase (BChE), synthesized in liver is also used as marker in the assessment of liver pathophysiology. This BChE enzyme in addition to its esterase activity has yet another enzymatic function designated as aryl acylamidase (AAA) activity. It is determined in in vitro based on the hydrolysis of the synthetic substrate o-nitroacetanilide. In the present study, human serum cholinesterase (BChE) activity was studied with respect to its AAA activity on the BChE protein (AAA(BChE)) in patients with liver disorders. AST and gamma GT values were taken into account in this study as known markers for liver disorders. Blood samples were grouped into 3 based on esterase activity associated with BChE protein. They are normal, low, and very low BChE activity but with markedly increased AST and gamma GT levels. These samples were tested for their respective AAA function. Association of AAA with BChE from samples was proved using BChE monoclonal antibody precipitation experiment. The absolute levels of AAA were increased as BChE activity decreased while deviating from normal samples and such deviation was directly proportional to the severity of the liver disorder. Differences between these groups became prominent after determining the ratios of AAA(BChE) to BChE activities. Samples showing very high AAA(BChE) to BChE ratio were also showing high to very high gamma GT values. These findings establish AAA(BChE) as an independently regulated enzymatic activity on BChE especially in liver disorders. Moreover, since neither the low esterase activity of BChE by itself nor increased levels of AST/gamma GT are sufficient pathological indicators, this pilot study merits replication with large sample numbers.

  11. Potentiation by cholinesterase inhibitors of cholinergic activity in rat isolated stomach and colon.

    PubMed

    Jarvie, Emma M; Cellek, Selim; Sanger, Gareth J

    2008-01-01

    Acetylcholinesterase (AChE) inhibitors stimulate gastrointestinal (GI) motility and are potential treatments of conditions associated with inadequate GI motility. The ability of itopride to facilitate neuronally (predominantly cholinergic) mediated contractions of rat isolated stomach, evoked by electrical field stimulation (EFS), has been compared with other cholinesterase inhibitors and with tegaserod, a clinically effective prokinetic and non-selective 5-HT(4) receptor agonist which also facilitates GI cholinergic function. Neostigmine greatly increased EFS-evoked contractions over a narrow concentration range (0.01-1 microM; 754+/-337% facilitation at 1 microM); higher concentrations (1, 3 microM) also increased muscle tension. Donepezil increased EFS-evoked contractions gradually over the full range of concentrations (0.01-10 microM; maximum increase 516+/-20% at 10 microM). Itopride increased the contractions even more gradually, rising to 188+/-84% at 10 microM. The butyrylcholinesterase inhibitor iso-OMPA 0.01-10 microM also increased EFS-evoked contractions, to a maximum of 36+/-5.0% at 10 microM, similar to that caused by tegaserod (35+/-5.2% increase at 1 microM). The effects of tegaserod, but not itopride were inhibited by the 5-HT(4) receptor antagonist SB-204070A 0.3 microM. In rat isolated colon, neostigmine was again the most efficacious, causing a defined maximum increase in EFS-evoked contractions (343+/-82% at 10 microM), without changing muscle tension. Maximum increases caused by donepezil and itopride were, respectively, 57.6+/-20 and 43+/-15% at 10 microM. These data indicate that the abilities of different AChE inhibitors to increase GI cholinergic activity differ markedly. Understanding the reasons is essential if AChE inhibitors are to be optimally developed as GI prokinetics.

  12. Novel Tacrine-Based Pyrano[3',4':5,6]pyrano[2,3-b]quinolinones: Synthesis and Cholinesterase Inhibitory Activity.

    PubMed

    Hariri, Roshanak; Afshar, Zahra; Mahdavi, Mohammad; Safavi, Maliheh; Saeedi, Mina; Najafi, Zahra; Sabourian, Reyhaneh; Karimpour-Razkenari, Elahe; Edraki, Najmeh; Moghadam, Farshad Homayouni; Shafiee, Abbas; Khanavi, Mahnaz; Akbarzadeh, Tahmineh

    2016-12-01

    In order to develop effective anti-cholinesterase compounds, a novel series of pyrano[3',4':5,6]pyrano[2,3-b]quinolinones were designed, synthesized, and evaluated in vitro against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). All derivatives showed very good AChE inhibitory (AChEI) activity (IC 50  = 0.37-5.62 μM) compared with rivastigmine (IC 50  = 11.07 μM). Among them, 11-amino-12-(2,3-dichlorophenyl)-3-methyl-7,8,9,10-tetrahydropyrano[3',4':5,6]pyrano[2,3-b]quinolin-1(12H)-one (6f) displayed the best inhibitory activity. However, most of the synthesized compounds showed no anti-BChE activity and compounds 6b and 6f were found to be only moderate inhibitors. The most potent anti-AChE compound 6f had low and moderate inhibitory activity and neuroprotective effects against beta-secretase (BACE1) and oxidative stress-induced cell death, respectively. Also, kinetic and molecular docking studies of binding interactions elucidated that compound 6f bound to both the catalytic anionic site (CAS) and peripheral anionic site (PAS) of AChE. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  13. Comparative Effects of Oral Chlorpyrifos Exposure on Cholinesterase Activity and Muscarinic Receptor Binding in Neonatal and Adult Rat Heart

    PubMed Central

    Howard, Marcia D.; Mirajkar, Nikita; Karanth, Subramanya; Pope, Carey N.

    2010-01-01

    Organophosphorus (OP) pesticides elicit acute toxicity by inhibiting acetylcholinesterase (AChE), the enzyme responsible for inactivating acetylcholine (ACh) at cholinergic synapses. A number of OP toxicants have also been reported to interact directly with muscarinic receptors, in particular the M2 muscarinic subtype. Parasympathetic innervation to the heart primarily regulates cardiac function by activating M2 receptors in the sinus node, atrial-ventricular node and conducting tissues. Thus, OP insecticides can potentially influence cardiac function in a receptor–mediated manner indirectly by inhibiting acetylcholinesterase and directly by binding to muscarinic M2 receptors. Young animals are generally more sensitive than adults to the acute toxicity of OP insecticides and age related differences in potency of direct binding to muscarinic receptors by some OP toxicants have been reported. We thus compared the effects of the common OP insecticide chlorpyrifos (CPF) on functional signs of toxicity and cardiac ChE activity and muscarinic receptor binding in neonatal and adult rats. Dosages were based on acute lethality (i.e., 0.5 and 1 × LD10: neonates, 7.5 and 15 mg/kg; adults, 68 and 136 mg/kg). Dose- and time-related changes in body weight and cholinergic signs of toxicity (involuntary movements) were noted in both age groups. With 1 × LD10, relatively similar maximal reductions in ChE activity (95%) and muscarinic receptor binding (≈ 30%) were noted, but receptor binding reductions appeared earlier in adults and were more prolonged in neonates. In vitro inhibition studies indicated that ChE in neonatal tissues was markedly more sensitive to inhibition by the active metabolite of chlorpyrifos (i.e., chlorpyrifos oxon, CPO) than enzyme in adult tissues (IC50 values: neonates, 17 nM; adults, 200 nM). Chelation of free calcium with EDTA had relatively little effect on in vitro cholinesterase inhibition, suggesting that differential A-esterase activity was not

  14. Genomic analysis of carboxyl/cholinesterase genes in the silkworm Bombyx mori

    PubMed Central

    2010-01-01

    Background Carboxyl/cholinesterases (CCEs) have pivotal roles in dietary detoxification, pheromone or hormone degradation and neurodevelopment. The recent completion of genome projects in various insect species has led to the identification of multiple CCEs with unknown functions. Here, we analyzed the phylogeny, expression and genomic distribution of 69 putative CCEs in the silkworm, Bombyx mori (Lepidoptera: Bombycidae). Results A phylogenetic tree of CCEs in B. mori and other lepidopteran species was constructed. The expression pattern of each B. mori CCE was also investigated by a search of an expressed sequence tag (EST) database, and the relationship between phylogeny and expression was analyzed. A large number of B. mori CCEs were identified from a midgut EST library. CCEs expressed in the midgut formed a cluster in the phylogenetic tree that included not only B. mori genes but also those of other lepidopteran species. The silkworm, and possibly also other lepidopteran species, has a large number of CCEs, and this might be a consequence of the large cluster of midgut CCEs. Investigation of intron-exon organization in B. mori CCEs revealed that their positions and splicing site phases were strongly conserved. Several B. mori CCEs, including juvenile hormone esterase, not only showed clustering in the phylogenetic tree but were also closely located on silkworm chromosomes. We investigated the phylogeny and microsynteny of neuroligins in detail, among many CCEs. Interestingly, we found the evolution of this gene appeared not to be conserved between B. mori and other insect orders. Conclusions We analyzed 69 putative CCEs from B. mori. Comparison of these CCEs with other lepidopteran CCEs indicated that they had conserved expression and function in this insect order. The analyses showed that CCEs were unevenly distributed across the genome of B. mori and suggested that neuroligins may have a distinct evolutionary history from other insect order. It is possible

  15. Treatment With Cholinesterase Inhibitors and Memantine of Patients in the Alzheimer’s Disease Neuroimaging Initiative

    PubMed Central

    Schneider, Lon S.; Insel, Philip S.; Weiner, Michael W.

    2011-01-01

    Objectives To assess the clinical characteristics and course of patients with mild cognitive impairment (MCI) and mild Alzheimer disease (AD) treated with cholinesterase inhibitors (ChEIs) and memantine hydrochloride. Design Cohort study. Setting The 59 recruiting sites for the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Participants Outpatients with MCI and AD in ADNI. Main Outcome Measures The AD Assessment Scale–cognitive subscale (ADAS-cog), Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR) scale, and Functional Activities Questionnaire (FAQ). Results A total of 177 (44.0%) of 402 MCI patients and 159 (84.6%) of 188 mild-AD patients were treated with ChEIs and 11.4% of MCI patients and 45.7% of AD patients with memantine at entry. Mild-cognitive-impairment patients who received ChEIs with or without memantine were more impaired, showed greater decline in scores, and progressed to dementia sooner than patients who did not receive ChEIs. Alzheimer-disease patients who received ChEIs and memantine took them longer, were more functionally impaired, and showed greater decline on the MMSE and CDR (but not on the ADAS-cog or FAQ) than those who received ChEIs only. Conclusions Academic physicians frequently prescribe ChEIs and memantine earlier than indicated in the US Food and Drug Administration–approved labeling to patients who are relatively more severely impaired or who are rapidly progressing toward cognitive impairment. The use of these medications in ADNI is associated with clinical decline and may affect the interpretation of clinical trial outcomes. Study Registration clinicalTrials.gov Identifier: NCT00106899 PMID:21220675

  16. Small Quaternary Inhibitors K298 and K524: Cholinesterases Inhibition, Absorption, Brain Distribution, and Toxicity.

    PubMed

    Karasova, Jana Zdarova; Hroch, Milos; Musilek, Kamil; Kuca, Kamil

    2016-02-01

    Inhibitors of acetylcholinesterase (AChE) may be used in the treatment of various cholinergic deficits, among them being myasthenia gravis (MG). This paper describes the first in vivo data for promising small quaternary inhibitors (K298 and K524): acute toxicity study, cholinesterase inhibition, absorption, and blood-brain barrier penetration. The newly prepared AChE inhibitors (bis-quinolinium and quinolinium compounds) possess a positive charge in the molecule which ensures that anti-AChE action is restricted to peripheral effect. HPLC-MS was used for determination of real plasma and brain concentration in the pharmacokinetic part of the study, and standard non-compartmental analysis was performed. The maximum plasma concentrations were attained at 30 min (K298; 928.76 ± 115.20 ng/ml) and 39 min (K524; 812.40 ± 54.96 ng/ml) after i.m. Both compounds are in fact able to target the central nervous system. It seems that the difference in the CNS distribution profile depends on an active efflux system. The K524 brain concentration was actively decreased to below an effective level; in contrast, K298 progressively accumulated in brain tissue. Peripheral AChE inhibitors are still first-line treatment in the mild forms of MG. Commonly prescribed carbamates have many severe side effects related to AChE carbamylation. The search for new treatment strategies is still important. Unlike carbamates, these new compounds target AChE via apparent π-π or π-cationic interaction aside at the AChE catalytic site.

  17. The effects of chlorpyrifos on cholinesterase activity and foraging behavior in the dragonfly, Anax junius (Odonata)

    USGS Publications Warehouse

    Brewer, S.K.; Atchison, G.J.

    1999-01-01

    We examined head capsule cholinesterase (ChE) and foraging behavior in nymphs of the dragonfly, Anax junius, exposed for 24 h to 0.2, 0.6 and 1.0 ??g l-1 of the organophosphorus (OP) insecticide, chlorpyrifos [O,O-diethyl O-(3,5,6-trichloro-2-pyridyl) phosphorothioate]. The invertebrate community is an important component of the structure and function of wetland ecosystems, yet the potential effects of insecticides on wetland ecosystems are largely unknown. Our objectives were to determine if exposure to environmentally realistic concentrations of chlorpyrifos affected foraging behavior and ChE activity in head capsules of dragonfly nymphs. Nymphs were exposed to different concentrations of chlorpyrifos and different prey densities in a factorial design. ChE activities and foraging behaviors of treated nymphs were not statistically different (p ??? 0.05) from control groups. Prey density effects exerted a greater effect on dragonfly foraging than toxicant exposures. Nymphs offered higher prey densities exhibited more foraging behaviors but also missed their prey more often. High variability in ChE activities within the control group and across treated groups precluded determination of relationships between ChE and foraging behaviors. It appears that A. junius is relatively tolerant of chlorpyrifos, although the concentrations we tested have been shown in other work to adversely affect the prey base; therefore the introduction of this insecticide may have indirect adverse affects on top invertebrate predators such as Odonata.

  18. Assessing capacity to consent to treatment with cholinesterase inhibitors in dementia using a specific and standardized version of the MacArthur Competence Assessment Tool (MacCAT-T).

    PubMed

    Mueller, Tanja; Haberstroh, Julia; Knebel, Maren; Oswald, Frank; Kaspar, Roman; Kemper, Christoph J; Halder-Sinn, Petra; Schroeder, Johannes; Pantel, Johannes

    2017-02-01

    The use of assessment tools has been shown to improve the inter-rater reliability of capacity assessments. However, instrument-based capacity assessments of people with dementia face challenges. In dementia research, measuring capacity with instruments like the MacArthur Competence Assessment Tool for Treatment (MacCAT-T) mostly employ hypothetical treatment vignettes that can overwhelm the abstraction capabilities of people with dementia and are thus not always suitable for this target group. The primary aim of this study was to provide a standardized real informed consent paradigm that enables the dementia-specific properties of capacity to consent to treatment in people with dementia to be identified in a real informed consent process that is both externally valid and ethically justifiable. The sample consisted of 53 people with mild to moderate dementia and a group of 133 people without cognitive impairment. Rather than using a hypothetical treatment vignette, we used a standardized version of the MacCAT-T to assess capacity to consent to treatment with cholinesterase inhibitors in people with dementia. Inter-rater reliability, item statistics, and psychometric properties were also investigated. Intraclass correlations (ICCs) (0.951-0.990) indicated high inter-rater reliability of the standardized real informed consent paradigm. In the dementia group, performance on different items of the MacCAT-T varied. Most people with dementia were able to express a treatment choice, and were aware of the need to take a tablet. Further information on the course of the disorder and the benefits and risks of the treatment were less understood, as was comparative reasoning regarding treatment alternatives. The standardized real informed consent paradigm enabled us to detect dementia-specific characteristics of patients' capacity to consent to treatment with cholinesterase inhibitors. In order to determine suitable enhanced consent procedures for this treatment, we recommend

  19. Evaluation of chlorpyrifos toxicity through a 28-day study: Cholinesterase activity, oxidative stress responses, parent compound/metabolite levels, and primary DNA damage in blood and brain tissue of adult male Wistar rats.

    PubMed

    Kopjar, Nevenka; Žunec, Suzana; Mendaš, Gordana; Micek, Vedran; Kašuba, Vilena; Mikolić, Anja; Lovaković, Blanka Tariba; Milić, Mirta; Pavičić, Ivan; Čermak, Ana Marija Marjanović; Pizent, Alica; Lucić Vrdoljak, Ana; Želježić, Davor

    2018-01-05

    In this 28 day-study, we evaluated the effects of the insecticide chlorpyrifos orally administered to Wistar rats at doses 0.160, 0.015, and 0.010 mg/kg b. w./day. Following treatment, total cholinesterase activity and activities of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) were measured. Oxidative stress responses were evaluated using a battery of endpoints to establish lipid peroxidation, changes in total antioxidant capacity, level of reactive oxygen species (ROS), glutathione (GSH) level and activities of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) and catalase. Using HPLC-UV DAD analysis, levels of the parent compound and its main metabolite 3,5,6-trichloro-2-pyridinol in plasma and brain tissue were measured. The genotoxic effect was estimated using alkaline comet assay in leukocytes and brain tissue. The exposure did not result in significant effects on total cholinesterase, AChE and BChE activity in plasma and brain tissue. Lipid peroxidation slightly increased both in plasma and brain tissue. Total antioxidant capacity, ROS and GSH levels were marginally influenced by the exposure. Treatment led to significant increases of GSH-Px activity in blood, SOD activity in erythrocytes and a slight increase of catalase activity in plasma. HPLC-UV DAD analysis revealed the presence of both the parent compound and its main metabolite in the plasma of all of the experimental animals and brain tissue of the animals treated at the two higher doses. All of the tested doses of chlorpyrifos were slightly genotoxic, both to leukocytes and brain tissue. Our results call for further research using other sensitive biomarkers of effect, along with different exposure scenarios. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Synthesis and Biological Assessment of Racemic Benzochromenopyrimidinimines as Antioxidant, Cholinesterase, and Aβ1-42 Aggregation Inhibitors for Alzheimer's Disease Therapy.

    PubMed

    Dgachi, Youssef; Ismaili, Lhassane; Knez, Damijan; Benchekroun, Mohamed; Martin, Hélène; Szałaj, Natalia; Wehle, Sarah; Bautista-Aguilera, Oscar M; Luzet, Vincent; Bonnet, Alexandre; Malawska, Barbara; Gobec, Stanislav; Chioua, Mourad; Decker, Michael; Chabchoub, Fakher; Marco-Contelles, José

    2016-06-20

    Given the complex nature of Alzheimer's disease (AD), compounds that are able to simultaneously address two or more AD-associated targets show greater promise for development into drugs for AD therapy. Herein we report an efficient two-step synthesis and biological evaluation of new racemic benzochromene derivatives as antioxidants, inhibitors of cholinesterase and β-amyloid (Aβ1-42 ) aggregation. Based on the results of the primary screening, we identified 15-(3-methoxyphenyl)-9,11,12,15-tetrahydro-10H,14H-benzo[5,6]chromeno[2,3-d]pyrido[1,2-a]pyrimidin-14-imine (3 e) and 16-(3-methoxyphenyl)-9,10,11,12,13,16-hexahydro-15H-benzo[5',6']chromeno[2',3':4,5]pyrimido[1,2-a]azepin-15-imine (3 f) as new potential multitarget-directed ligands for AD therapy. Further in-depth biological analysis showed that compound 3 f is a good human acetylcholinesterase inhibitor [IC50 =(0.36±0.02) μm], has strong antioxidant activity (3.61 μmol Trolox equivalents), and moderate Aβ1-42 antiaggregating power (40.3 %). © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  1. Dual Use of Bladder Anticholinergics and Cholinesterase Inhibitors: Long-Term Functional and Cognitive Outcomes

    PubMed Central

    Sink, Kaycee M.; Thomas, Joseph; Xu, Huiping; Craig, Bruce; Kritchevsky, Steven; Sands, Laura P.

    2015-01-01

    OBJECTIVES To determine the cognitive and functional consequences of dual use of cholinesterase inhibitors (ChIs) and the bladder anticholinergics oxybutynin or tolterodine. DESIGN Prospective cohort study. SETTING Nursing homes (NHs) in the state of Indiana. PARTICIPANTS Three thousand five hundred thirty-six Medicaid-eligible NH residents aged 65 and older taking a ChI between January 1, 2003, and December 31, 2004. Residents were excluded if they were taking an anticholinergic other than oxybutynin or tolterodine. MEASUREMENTS Indiana Medicaid claims data were merged with data from the Minimum Data Set (MDS). Repeated-measures analyses were performed to assess the effects of dual therapy on change in cognitive function measured using the MDS Cognition Scale (MDS-COGS; scored 0–10) and change in activity of daily living (ADL) function using the seven ADL items in the MDS (scored 0–28). Potential covariates included age, sex, race, number of medications, and Charlson Comorbidity Index score. RESULTS Three hundred seventy-six (10.6%) residents were prescribed oxybutynin or tolterodine concomitantly with a ChI. In residents in the top quartile of ADL function, ADL function declined an average of 1.08 points per quarter when not taking bladder anticholinergics (ChI alone), compared with 1.62 points per quarter when taking dual therapy, a 50% greater rate in quarterly decline in ADL function (P =.01). There was no excess decline attributable to dual therapy in MDS-COGS scores or in ADL function for residents who started out with lower functioning. CONCLUSION In higher-functioning NH residents, dual use of ChIs and bladder anticholinergics may result in greater rates of functional decline than use of ChIs alone. The MDS-COGS may not be sensitive enough to detect differences in cognition due to dual use. PMID:18384584

  2. Effects of the herbicide Roundup on the polychaeta Laeonereis acuta: Cholinesterases and oxidative stress.

    PubMed

    de Melo Tarouco, Fábio; de Godoi, Filipe Guilherme Andrade; Velasques, Robson Rabelo; da Silveira Guerreiro, Amanda; Geihs, Marcio Alberto; da Rosa, Carlos Eduardo

    2017-01-01

    Glyphosate based herbicides, including Roundup, are widely employed in agriculture and urban spaces. The objective of this study was to evaluate the toxicological effects of Roundup on the estuarine polychaeta Laeonereis acuta. Biomarkers of oxidative stress as well as acetylcholinesterase and propionilcholinesterase activities were analyzed. Firstly, the LC 50 96h for L. acuta was established (8.19mg/L). After, the animals were exposed to two Roundup concentrations: 3.25mg/L (non-observed effect concentration - NOEC) and 5.35mg/L (LC 10 ) for 24h and 96h. Oxygen consumption was determined and the animals were divided into three body regions (anterior, middle and posterior) for biochemical analysis. An inhibition of both cholinesterase isoforms were observed in animals exposed to both Roundup concentrations after 96h. A significant reactive oxygen species (ROS) reduction was observed in the posterior region of animals in both periods, while antioxidant capacity against peroxyl radicals (ACAP) was reduced in the posterior region of animals exposed for 24h. Considering the antioxidant defense system, both GSH levels and enzyme activities (catalase, superoxide dismutase, glutathione s-transferase, glutathione peroxidase and glutamate cysteine ligase) were not altered after exposure. Lipid peroxidation was reduced in all analyzed body regions in both Roundup concentrations after 24h. Animals exposed to the highest concentration presented a reduction in lipid peroxidation in the anterior region after 96h, while animals exposed to the lowest concentration presented a reduction in the middle region. Overall results indicate that Roundup exposure presents toxicity to L. acuta, causing a disruption in ROS and ACAP levels as well as affects the cholinergic system of this invertebrate species. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Characterizing biological variability in livestock blood cholinesterase activity for biomonitoring organophosphate nerve agent exposure

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Halbrook, R.S.; Shugart, L.R.; Watson, A.P.

    1992-09-01

    A biomonitoring protocol, using blood cholinesterase (ChE) activity in livestock as a monitor of potential organophosphate nerve agent exposure during the planned destruction of US unitary chemical warfare agent stockpiles, is described. The experimental design included analysis of blood ChE activity in individual healthy sheep, horses, and dairy and beef cattle during a 10- to 12-month period. Castrated and sexually intact males, pregnant and lactating females, and adult and immature animals were examined through at least one reproductive cycle. The same animals were used throughout the period of observation and were not exposed to ChE-inhibiting organophosphate or carbamate compounds. Amore » framework for an effective biomonitoring protocol within a monitoring area includes establishing individual baseline blood ChE activity for a sentinel group of 6 animals on the bases of blood samples collected over a 6-month period, monthly collection of blood samples for ChE-activity determination during monitoring, and selection of adult animals as sentinels. Exposure to ChE-inhibiting compounds would be suspected when all blood ChE activity of all animals within the sentinel group are decreased greater than 20% from their own baseline value. Sentinel species selection is primarily a logistical and operational concern; however, sheep appear to be the species of choice because within-individual baseline ChE activity and among age and gender group ChE activity in sheep had the least variability, compared with data from other species. This protocol provides an effective and efficient means for detecting abnormal depressions in blood ChE activity in livestock and can serve as a valuable indicator of the extent of actual plume movement and/or deposition in the event of organophosphate nerve agent release.« less

  4. Cholinesterases and cell proliferation in "nonstratified" and "stratified" cell aggregates from chicken retina and tectum.

    PubMed

    Vollmer, G; Layer, P G

    1987-12-01

    Dissociated single cells from chicken retina or tectum kept in rotation-mediated cell culture aggregate, proliferate and establish a certain degree of histotypical cell-to-cell relationships ("sorting out"), but these systems never form highly laminated aggregates ("nonstratified" R- and T-aggregates). In contrast, a mixture of retinal plus pigment epithelial cells forms highly "stratified" aggregates ("RPE-aggregates", see Vollmer et al. 1984). The present comparative study of "stratified" and "nonstratified" aggregates enables us to investigate the process of cell proliferation uncoupled from that of tissue stratification. Here we try to relate these two basic neurogenetic processes with patterns of expression of cholinesterases (AChE, BChE) during formation of both types of aggregates. During early aggregate formation, in both "stratified" and "nonstratified" aggregates an increased butyrylcholinesterase activity is observed close to mitotically active cells. Quantitatively both phenomena show their maxima after 2-3 days in culture. In contrast, AChE-expression in all systems increases with incubation time. In nonproliferative areas, in the center of RPE-aggregates, the formation of plexiform layers is characterized initially by weak BChE- and then strong AChE-activity. These areas correspond with the inner (IPL) and outer (OPL) plexiform layers of the retina in vivo. Although by sucrose gradient centrifugation we find that the 6S- and the fiber-associated 11S-molecules of AChE are present in all types of aggregates, during the culture period the ratio of 11S/6S-forms increases only in RPE-aggregates, which again indicates the advanced degree of differentiation within these aggregates.(ABSTRACT TRUNCATED AT 250 WORDS)

  5. Long-term effects of the concomitant use of memantine with cholinesterase inhibition in Alzheimer disease

    PubMed Central

    Lopez, O L; Becker, J T; Wahed, A S; Saxton, J; Sweet, R A; Wolk, D A; Klunk, W; DeKosky, S T

    2010-01-01

    Background Patients using cholinesterase inhibitors (ChEIs) have a delay in nursing home (NH) admission compared with those who were not using the medication. There are no long-term studies of the effects of memantine in combination with ChEIs use in Alzheimer disease (AD). This study was conducted to examine the effects of ChEIs and memantine on time to death and time to NH admission. Methods Time to NH admission and death was examined in 943 probable AD patients who had at least a 1-year follow-up evaluation. Of these patients, 140 (14.9%) used both ChEIs and memantine, 387 (45.0%) used only ChEIs, and 416 (40.1%) used neither. The mean (SD) follow-up time was 62.3 (35.8) months. The analysis was conducted with multivariable Cox proportional hazard models controlling for critical covariates (ie, age, education level, gender, severity of the dementia, hypertension, diabetes mellitus, heart disease, psychiatric symptoms and use of psychotropic medications). Results Compared with those who never used cognitive enhancers, patients who used ChEIs had a significant delay in NH admission (HR: 0.37, 95% CI 0.27 to 0.49); this effect was significantly augmented with the addition of memantine (HR: 0.29, 95% CI 0.11 to 0.72) (memantine+ChEI vs ChEI alone). ChEIs alone, or in combination with memantine had no significant association on time to death. Conclusions This observational study revealed that the addition of the NMDA receptor antagonist memantine to the treatment of AD with ChEI significantly altered the treated history of AD by extending time to nursing home admission. PMID:19204022

  6. The output per stimulus of acetylcholine from cerebral cortical slices in the presence or absence of cholinesterase inhibition

    PubMed Central

    Bourdois, P.S.; Mitchell, J.F.; Somogyi, G.T.; Szerb, J.C.

    1974-01-01

    1 The release of endogenous acetylcholine (ACh) from cerebral cortical slices stimulated at 0.25, 1, 4, 16 and 64 Hz was measured in the presence either of physostigmine or of physostigmine and atropine. 2 Atropine potentiated the evoked release of endogenous ACh especially at low frequencies resulting in an output per stimulus which sharply declined with increasing frequency of stimulation, while in the absence of atropine the output of ACh per stimulus was low and fairly constant. 3 The evoked release of [3H]-ACh per stimulus following the incubation of the slices with [3H]-choline, as estimated by means of rate constants of the evoked release of total radioactivity, showed a frequency dependence similar to endogenous ACh when the two were tested under identical conditions. 4 In the absence of an anticholinesterase the evoked release of [3H]-ACh per stimulus was dependent on frequency of stimulation in a similar way to that in the presence of physostigmine and atropine. 5 Results suggest that under physiological conditions, i.e. in the absence of an anti-cholinesterase, the release of ACh per stimulus decreases with increasing frequency of stimulation and that this decrease is due to a lag in the mobilization of stored ACh rather than in the synthesis of new ACh. PMID:4455327

  7. Quinolinic Carboxylic Acid Derivatives as Potential Multi-target Compounds for Neurodegeneration: Monoamine Oxidase and Cholinesterase Inhibition.

    PubMed

    Khan, Nehal A; Khan, Imtiaz; Abid, Syed M A; Zaib, Sumera; Ibrar, Aliya; Andleeb, Hina; Hameed, Shahid; Iqbal, Jamshed

    2018-01-01

    Parkinson's disease (PD), a debilitating and progressive disorder, is among the most challenging and devastating neurodegenerative diseases predominantly affecting the people over 60 years of age. To confront PD, an advanced and operational strategy is to design single chemical functionality able to control more than one target instantaneously. In this endeavor, for the exploration of new and efficient inhibitors of Parkinson's disease, we synthesized a series of quinoline carboxylic acids (3a-j) and evaluated their in vitro monoamine oxidase and cholinesterase inhibitory activities. The molecular docking and in silico studies of the most potent inhibitors were performed to identify the probable binding modes in the active site of the monoamine oxidase enzymes. Moreover, molecular properties were calculated to evaluate the druglikeness of the compounds. The biological evaluation results revealed that the tested compounds were highly potent against monoamine oxidase (A & B), 3c targeted both the isoforms of MAO with IC50 values of 0.51 ± 0.12 and 0.51 ± 0.03 µM, respectively. The tested compounds also demonstrated high and completely selective inhibitory action against acetylcholinesterase (AChE) with IC50 values ranging from 4.36 to 89.24 µM. Among the examined derivatives, 3i was recognized as the most potent inhibitor of AChE with an IC50 value of 4.36 ± 0.12 ±µM. The compounds appear to be promising inhibitors and could be used for the future development of drugs targeting neurodegenerative disorders. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  8. Design, synthesis and evaluation of novel dual monoamine-cholinesterase inhibitors as potential treatment for Alzheimer's disease.

    PubMed

    Liu, Wei; Lang, Ming; Youdim, Moussa B H; Amit, Tamar; Sun, Yewei; Zhang, Zaijun; Wang, Yuqiang; Weinreb, Orly

    2016-10-01

    Current novel therapeutic approach suggests that multifunctional compounds with diverse biological properties and a single bioavailability and pharmacokinetic metabolism, will produce higher significant advantages in treatment of neurodegenerative diseases, such as Alzheimer's disease (AD). Based on this rational, a new class of cholinesterase (ChE)-monoamine oxidase (MAO) inhibitors were designed and synthesized by amalgamating the propargyl moiety of the irreversible selective MAO-B inhibitor, neuroprotective/neurorestorative anti-Parkinsonian drug, rasagiline, into the "N-methyl" position of the ChE inhibitor, anti-AD drug rivastigmine. Initially, we examined the MAO and ChE inhibitory effect of these novel compounds, MT series in vitro and in vivo. Among MT series, MT-031 exhibited higher potency as a dual MAO-A and ChE inhibitor compared to other compounds in acute-treated mice. Additionally, MT-031 was found to increase the striatal levels of dopamine (DA), serotonin (5-HT) and norepinephrine (NE), and prevent the metabolism of DA and 5-HT. Finally, we have demonstrated that MT-031 exerted neuroprotective effect against H2O2-induced neurotoxicity and reactive oxygen species generation in human neuroblastoma SH-SY5Y cells. These findings provide evidence that MT-031 is a potent brain permeable novel multifunctional, neuroprotective and MAO-A/ChE inhibitor, preserves in one molecule entity some of the beneficial properties of its parent drugs, rasagiline and rivastigmine, and thus may be indicated as novel therapeutic approach for AD. Copyright © 2016 Elsevier Ltd. All rights reserved.

  9. AGE-RELATED BRAIN CHOLINESTERASE INHIBITION KINETICS FOLLOWING IN VITRO INCUBATION WITH CHLORPYRIFOS-OXON AND DIAZINON-OXON

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Kousba, Ahmed A.; Poet, Torka S.; Timchalk, Chuck

    2007-01-01

    Chlorpyrifos and diazinon are two commonly used organophosphorus (OP) insecticides, and their primary mechanism of action involves the inhibition of acetylcholinesterase (AChE) by their metabolites chlorpyrifos-oxon (CPO) and diazinon-oxon (DZO), respectively. The study objectives were to assess the in vitro age-related inhibition kinetics of neonatal rat brain cholinesterase (ChE) by estimating the bimolecular inhibitory rate constant (ki) values for CPO and DZO. Brain ChE inhibition and ki values following CPO and DZO incubation with neonatal Sprague-Dawley rats rat brain homogenates were determined at post natal day (PND) -5, -12 and -17 and compared with the corresponding inhibition and ki valuesmore » obtained in the adult rat. A modified Ellman method was utilized for measuring the ChE activity. Chlorpyrifos-oxon resulted in greater ChE inhibition than DZO consistent with the estimated ki values of both compounds. Neonatal brain ChE inhibition kinetics exhibited a marked age-related sensitivity to CPO, where the order of ChE inhibition was PND-5 > PND-7 > PND-17 with ki values of 0.95, 0.50 and 0.22 nM-1hr-1, respectively. In contrast, DZO did not exhibit an age-related inhibition of neonatal brain ChE, and the estimated ki value at all PND ages was 0.02 nM-1hr-1. These results demonstrated an age- and chemical-related OP-selective inhibition of rat brain ChE which may be critically important in understanding the potential sensitivity of juvenile humans to specific OP exposures.« less

  10. Organophosphate and carbamate insecticides in agricultural waters and cholinesterase (ChE) inhibition in common carp (Cyprinus carpio)

    USGS Publications Warehouse

    Gruber, S.J.; Munn, M.D.

    1998-01-01

    Cholinesterase (ChE) activity was used as a biomarker for assessing exposure of common carp (Cyprinus carpio) to organophosphate and carbamate insecticides from irrigated agricultural waters. Carp were collected from a lake (Royal Lake) that receives most of its water from irrigation return flows and from a reference lake (Billy Clapp Lake) outside of the irrigation system. Results indicated that the mean whole-brain ChE activity of carp from Royal Lake (3.47 μmol/min/g tissue) was 34.2% less than that of carp from Billy Clapp Lake (5.27 μmol/min/g tissue) (p = 0.003). The depressed ChE activity in brain tissue of Royal Lake carp was in response to ChE-inhibiting insecticides detected in water samples in the weeks prior to tissue sampling; the most frequently detected insecticides included chlorpyrifos, azinphos-methyl, carbaryl, and ethoprop. Neither sex nor size appears to be a covariable in the analysis; ChE activity was not correlated with fish length or weight in either lake and there was no significant difference in ChE activity between the two sexes within each lake. Although organophosphate and carbamate insecticides can break down rapidly in the environment, this study suggests that in agricultural regions where insecticides are applied for extended periods of the year, nontarget aquatic biota may be exposed to high levels of ChE-inhibiting insecticides for a period of several months.

  11. Cholinesterase inhibition modulates visual and attentional brain responses in Alzheimer's disease and health.

    PubMed

    Bentley, Paul; Driver, Jon; Dolan, Ray J

    2008-02-01

    Visuo-attentional deficits occur early in Alzheimer's disease (AD) and are considered more responsive to pro-cholinergic therapy than characteristic memory disturbances. We hypothesised that neural responses in AD during visuo-attentional processing would be impaired relative to controls, yet partially susceptible to improvement with the cholinesterase inhibitor physostigmine. We studied 16 mild AD patients and 17 age-matched healthy controls, using fMRI-scanning to enable within-subject placebo-controlled comparisons of effects of physostigmine on stimulus- and attention- related brain activations, plus between-group comparisons for these. Subjects viewed face or building stimuli while performing a shallow judgement (colour of image) or a deep judgement (young/old age of depicted face or building). Behaviourally, AD subjects performed slower than controls in both tasks, while physostigmine benefited the patients for the more demanding age-judgement task. Stimulus-selective (face minus building, and vice versa) BOLD signals in precuneus and posterior parahippocampal cortex were attenuated in patients relative to controls, but increased following physostigmine. By contrast, face-selective responses in fusiform cortex were not impaired in AD and showed decreases following physostigmine for both groups. Task-dependent responses in right parietal and prefrontal cortices were diminished in AD but improved following physostigmine. A similar pattern of group and treatment effects was observed in two extrastriate cortical regions that showed physostigmine-induced enhancement of stimulus-selectivity for the deep versus shallow task. Finally, for the healthy group, physostigmine decreased stimulus and task-dependent effects, partly due to an exaggeration of selectivity during the shallow relative to deep task. The differences in brain activations between groups and treatments were not attributable merely to performance (reaction time) differences. Our results demonstrate

  12. Novel tacrine-1,2,3-triazole hybrids: In vitro, in vivo biological evaluation and docking study of cholinesterase inhibitors.

    PubMed

    Najafi, Zahra; Mahdavi, Mohammad; Saeedi, Mina; Karimpour-Razkenari, Elahe; Asatouri, Raymond; Vafadarnejad, Fahimeh; Moghadam, Farshad Homayouni; Khanavi, Mahnaz; Sharifzadeh, Mohammad; Akbarzadeh, Tahmineh

    2017-01-05

    A new series of tacrine-1,2,3-triazole hybrids were designed, synthesized, and evaluated as potent dual cholinesterase inhibitors. Most of synthesized compounds showed good in vitro inhibitory activities toward both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Among them, 7-chloro-N-((1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)-1,2,3,4-tetrahydroacridin-9-amine (5l) was found to be the most potent anti-AChE derivative (IC 50  = 0.521 μM) and N-((1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)-1,2,3,4-tetrahydroacridin-9-amine (5j) demonstrated the best anti-BChE activity (IC 50  = 0.055 μM). In vivo studies of compound 5l in Morris water maze task confirmed memory improvement in scopolamine-induced impairment. Also, molecular modeling and kinetic studies showed that compounds 5l and 5j bound simultaneously to the peripheral anionic site (PAS) and catalytic sites (CS) of the AChE and BChE. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  13. Structure-Based Design and Optimization of Multitarget-Directed 2H-Chromen-2-one Derivatives as Potent Inhibitors of Monoamine Oxidase B and Cholinesterases.

    PubMed

    Farina, Roberta; Pisani, Leonardo; Catto, Marco; Nicolotti, Orazio; Gadaleta, Domenico; Denora, Nunzio; Soto-Otero, Ramon; Mendez-Alvarez, Estefania; Passos, Carolina S; Muncipinto, Giovanni; Altomare, Cosimo D; Nurisso, Alessandra; Carrupt, Pierre-Alain; Carotti, Angelo

    2015-07-23

    The multifactorial nature of Alzheimer's disease calls for the development of multitarget agents addressing key pathogenic processes. To this end, by following a docking-assisted hybridization strategy, a number of aminocoumarins were designed, prepared, and tested as monoamine oxidases (MAOs) and acetyl- and butyryl-cholinesterase (AChE and BChE) inhibitors. Highly flexible N-benzyl-N-alkyloxy coumarins 2-12 showed good inhibitory activities at MAO-B, AChE, and BChE but low selectivity. More rigid inhibitors, bearing meta- and para-xylyl linkers, displayed good inhibitory activities and high MAO-B selectivity. Compounds 21, 24, 37, and 39, the last two featuring an improved hydrophilic/lipophilic balance, exhibited excellent activity profiles with nanomolar inhibitory potency toward hMAO-B, high hMAO-B over hMAO-A selectivity and submicromolar potency at hAChE. Cell-based assays of BBB permeation, neurotoxicity, and neuroprotection supported the potential of compound 37 as a BBB-permeant neuroprotective agent against H2O2-induced oxidative stress with poor interaction as P-gp substrate and very low cytotoxicity.

  14. Organophosphate-Related Alterations in Myelin and Axonal Transport in the Living Mammalian Brain

    DTIC Science & Technology

    2014-10-01

    between blood cholinesterase activity and neurobehavioral deficits (Rohlman et al., 2011). Finally, one additional argument against the premise that AChE...baseline scan (repeated exposure CPF group only). 2.4 Cholinesterase activity Cholinesterase activity was assessed in brain using the method of...Moser VC.2006. Behavioral toxicity of cholinesterase inhibitors. In: Gupta, RC., editor. Toxicology of Organophosphate and Carbamate Compounds

  15. Aflatoxins produced by Aspergillus parasiticus present in the diet of quails increase the activities of cholinesterase and adenosine deaminase.

    PubMed

    da Silva, Aleksandro Schafer; Santurio, Janio M; Roza, Lenilson F; Bottari, Nathieli B; Galli, Gabriela M; Morsch, Vera M; Schetinger, Maria Rosa C; Baldissera, Matheus D; Stefani, Lenita M; Radavelli, Willian M; Tomasi, Thainã; Boiago, Marcel M

    2017-06-01

    The aim of this study was to evaluate the effects of aflatoxins on cholinesterases (acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), and adenosine deaminase (ADA) activities in quails. For this, twenty male quails were randomly distributed into two groups (n = 10 each): the group A was composed by quails that received feed without aflatoxin (the control group); while the group B was composed by quails that received feed contaminated with 200 ppm/kg of feed of aflatoxin. On day 20, the animals were euthanized to measure the activities of AChE (total blood and brain), BChE (serum) and ADA (serum, liver, and brain), as well as for histopathological analyses (liver and intestine). AChE, BChE, and ADA levels increased in animals intoxicated by aflatoxin compared to the control group. The presence of aflatoxin lead to severe hydropic degeneration of hepatocytes and small focus of hepatocyte necrosis. In conclusion, aflatoxins poisoning increased AChE, BChE, and ADA activities, suggesting the involvement of these enzymes during this type of intoxication, in addition to the fact that they are well known molecules that participate in physiological and pathological events as inflammatory mediators. In summary, increased AChE, BChE and ADA activities contribute directly to the inflammatory process and tissue damage, and they might be involved in disease development. Copyright © 2017 Elsevier Ltd. All rights reserved.

  16. Biomonitoring of Organophosphorus Agent Exposure by Reactivation of Cholinesterase Enzyme Based on Carbon Nanotube-Enhanced Flow-Injection Amperometric Detection

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Du, Dan; Wang, Jun; Smith, Jordan N.

    2009-11-15

    A portable, rapid, and sensitive assessment of sub-clinical organophosphorus (OPs) agent exposure based on reactivation of cholinesterase (ChE) from OP-inhibited ChE using rat saliva (in vitro) was developed using an electrochemical sensor coupled with a microflow-injection system. The sensor was based on a carbon nanotube (CNT)-modified screen printed carbon electrode (SPE), which was integrated into a flow cell. Due to the extent of inter-individual ChE activity variability, ChE biomonitoring often requires an initial base-line determination (non-inhibited) of enzyme activity which is then directly compared with activity after OP exposure. This manuscript described an alternative strategy where reactivation of the phosphorylatedmore » enzyme was exploited to enable measurement of both inhibited and baseline ChE activity (i.e. after reactivation) in the same sample. The use of CNT makes the electrochemical detection of the products from enzymatic reactions more feasible with extremely high sensitivity and at low potentials. Paraoxon was selected as a model OP compound for in vitro inhibition studies. Some experiment parameters, (e.g. inhibition and reactivation times), have been optimized such that, 92 - 95% ChE reactivation can be achieved over a broad range of ChE inhibition (5 - 94 %) with paraoxon. The extent of enzyme inhibition using this electrochemical sensor correlates well with conventional enzyme activity measurements.« less

  17. Synthesis, characterization, X-ray crystal structures of heterocyclic Schiff base compounds and in vitro cholinesterase inhibition and anticancer activity

    NASA Astrophysics Data System (ADS)

    Arafath, Md. Azharul; Adam, Farook; Al-Suede, Fouad Saleih R.; Razali, Mohd R.; Ahamed, Mohamed B. Khadeer; Abdul Majid, Amin Malik Shah; Hassan, Mohd Zaheen; Osman, Hasnah; Abubakar, Saifullah

    2017-12-01

    Four heterocyclic embedded Schiff base derivatives (1-4) were synthesized and characterized by melting point, elemental analysis, FTIR, 1H, 13C NMR, UV-Visible spectral data. The structures of compounds 1, 2 and 4 were successfully established through single crystal X-ray diffraction analysis. In vitro cholinesterase inhibition assays showed that the cyclized derivative 1 displayed higher BuChE enzyme inhibitory activity with IC50 value of 1.45 ± 0.09 μM. The anti-proliferative efficacies of the compounds were also evaluated using human colorectal HCT 116 and breast MCF-7 adenocarcinoma cell lines. In addition, a human normal endothelial cell line (Ea.hy926) was also tested to assess the safety and selectivity of the compounds towards normal and cancer cells, respectively. Among the compounds tested, compound 2 displayed potent cytotoxic effect (IC50 = 34 μM) against HCT 116 cells with highest selectivity index of 3.1 with respect to the normal endothelial cells. Whereas, compound 4 exhibited significant anti-proliferative effect (IC50 = 21.1 μM) against MCF-7 cells with highest selectivity index of 3.3 with respect to the normal endothelial cells. The docking result of these compounds against hAChE showed potent activities with different binding modes. These compounds could be a promising pharmacological agent to treat cancer and Alzheimer's disease.

  18. Effect of Different Administration Paradigms on Cholinesterase Inhibition following Repeated Chlorpyrifos Exposure in Late Preweanling Rats

    PubMed Central

    Carr, Russell L.; Nail, Carole A.

    2008-01-01

    Chlorpyrifos (CPS) is widely used in agricultural settings and residue analysis has suggested that children in agricultural communities are at risk of exposure. This has resulted in a large amount of literature investigating the potential for CPS-induced developmental neurotoxic effects. Two developmental routes of administration of CPS are orally in corn oil at a rate of 0.5 ml/kg and subcutaneously in dimethyl sulfoxide (DMSO) at a rate of 1.0 ml/kg. For comparison between these methods, rat pups were exposed daily from days 10 to 16 to CPS (5 mg/kg) either orally dissolved in corn oil or subcutaneously dissolved in DMSO, both at rates of either 0.5 or 1.0 ml/kg. A representative vehicle/route group was present for each treatment. Both the low and high volume CPS in DMSO subcutaneous groups were lower than that of the low and high volume CPS in oil oral groups. At 4 h following the final administration, serum carboxylesterase was inhibited > 90% with all treatments. For cholinesterase activity in the cerebellum, medulla-pons, forebrain, and hindbrain, and serum, inhibition in the CPS-oil groups was similar and inhibition in the CPS-DMSO groups was similar. However, significantly greater inhibition was present in the high volume CPS-DMSO group as compared to the CPS-oil groups. Inhibition in the low volume CPS-DMSO group was generally between that in the CPS-oil groups and the high volume CPS-DMSO group. These data suggest that using DMSO as a vehicle for CPS may alter the level of brain ChE inhibition. PMID:18703558

  19. Elevated cholinesterase activity and increased urinary excretion of inorganic fluorides in the workers producing fluorine-containing plastic (polytetrafluoroethylene)

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Baohui Xu; Jiusun Zhang; Guaogeng Mao

    1992-07-01

    Fluoropolymers are widely used in thermal and electrical industries. Polytetrafluoroethylene (PTFE) plastic is a typical one. During its production, workers are occupationally exposed to many organic fluorides, especially tetrafluoroethylene, chlorodifluoromethane, PTFE and its thermal decomposition products. Of these compounds, it has been documented that following inhalation of combustion products of PTFE the focal hemorrhages, edema, fibrin deposition in lungs and renal infarcts were observed in rats. Odum and Green have demonstrated a marked damage to proximal tubule of kidney with no effects on the liver in rats exposed to 6000 ppm tetrafluoroethylene for 6 hr. The investigations of the hazardsmore » of these compounds to workers have been mainly focused on acute toxicity. There have been some reports that polymers and its pyrolysis caused polymer fume fever and pulmonary edema. In practice, workers engaged in PTFE manufacture are chronically exposed to the above-mentioned chemicals, but little was known about the hazards ascribed to these chemicals. To clarify the influences of the exposed chemicals on health in PTFE production we conducted a mass survey investigation in a PTFE production factory. As a result, in addition to the nephrotoxicity characterized by elevated ALP and NAG activities in urine, more interestingly, we have also found a reversible increase in cholinesterase (ChE) activity and enhanced urinary excretion of inorganic fluorides in workers engaged in PTFE production. We report here these findings and discuss their physiological significance. 18 refs., 4 tabs.« less

  20. The first evidence of cholinesterases in skin mucus of carps and its applicability as biomarker of organophosphate exposure.

    PubMed

    Nigam, Ashwini Kumar; Srivastava, Nidhi; Rai, Amita Kumari; Kumari, Usha; Mittal, Ajay Kumar; Mittal, Swati

    2014-05-01

    The presence of cholinesterase (ChE) activity in skin mucus of three carps, Cirrhinus mrigala, Labeo rohita, and Catla catla and its applicability as biomarker of the organophosphorus insecticide exposure were investigated. Biochemical characterization, using specific substrates and inhibitors, indicated that measured esterase activity in skin mucus was mainly owing to ChEs. Significant difference in the proportion of acetylcholinesterase and butyrylcholinesterase activities was observed in skin mucus of three carps. Enzyme kinetic analysis, using the substrate acetylthiocholine iodide revealed significantly high Vmax value in C. catla compared to that in L. rohita and C. mrigala. In contrast, Vmax value using the substrate butyrylthiocholine iodide was significantly high in C. mrigala than in L. rohita and C. catla. In vitro treatment of skin mucus of three carps, with the organophosphorus insecticide Nuvan®, showed strong inhibition of ChE activities. In vivo experiments conducted using C. mrigala and exposing the fish to the sublethal test concentrations (5 and 15 mg/L) of the insecticide also revealed significant inhibition of ChE activity in mucus. In C. mrigala, exposed to the sublethal test concentrations of the insecticide for 4 days and then kept for recovery for 16 days, mucus ChE activity recovered to the control level. Thus, ChE activity in skin mucus could be considered a good biomarker of the organophosphorus insecticide exposure to fish and a useful tool in monitoring environmental toxicity. Copyright © 2012 Wiley Periodicals, Inc., a Wiley company.

  1. Does the cholinesterase inhibitor, donepezil, benefit both declarative and non-declarative processes in mild to moderate Alzheimer's disease?

    PubMed

    Winstein, Carolee J; Bentzen, Kirk R; Boyd, Lara; Schneider, Lon S

    2007-07-01

    Previous research suggests separate neural networks for implicit (non-declarative) and explicit (declarative) memory processes. A core cognitive impairment in mild to moderate Alzheimer's disease (AD) is a pronounced declarative memory and learning deficit with relative preservation of non-declarative memory. Cholinesterase inhibitors has been purported to enhance cognitive function, and previous clinical trials consistently showed that donepezil, a reversible inhibitor of acetylcholinesterase (AChE), led to statistically significant improvements in cognition and patient function. This prospective pilot study is a randomized, double blind, placebo-controlled clinical trial investigating 10 patients with AD. Our purpose was to examine the relationship between declarative and non-declarative capability with particular emphasis on implicit sequence learning. Patients were assessed at baseline and again at 4-weeks. After participants' baseline data were obtained, each was double-blindly randomized to one of two groups: donepezil or placebo. At baseline participants were tested with two outcome measures (Serial Reaction Time Task, Alzheimer's Disease Assessment Scale-Cognitive Subscale). Participants were given either 5 mg donepezil or an identically appearing placebo to be taken nightly for 4 weeks (28 tablets), and then retested. The donepezil group demonstrated a greater likelihood of increases in both non-declarative and declarative processes. The placebo group was mixed without clearly definable trends or patterns. When the data were examined for coincidental changes in the two outcome measures together they are suggestive of a benefit from donepezil treatment for non-declarative and declarative processes.

  2. The Glutathione-S-Transferase, Cytochrome P450 and Carboxyl/Cholinesterase Gene Superfamilies in Predatory Mite Metaseiulus occidentalis

    PubMed Central

    Hoy, Marjorie A.

    2016-01-01

    Pesticide-resistant populations of the predatory mite Metaseiulus (= Typhlodromus or Galendromus) occidentalis (Arthropoda: Chelicerata: Acari: Phytoseiidae) have been used in the biological control of pest mites such as phytophagous Tetranychus urticae. However, the pesticide resistance mechanisms in M. occidentalis remain largely unknown. In other arthropods, members of the glutathione-S-transferase (GST), cytochrome P450 (CYP) and carboxyl/cholinesterase (CCE) gene superfamilies are involved in the diverse biological pathways such as the metabolism of xenobiotics (e.g. pesticides) in addition to hormonal and chemosensory processes. In the current study, we report the identification and initial characterization of 123 genes in the GST, CYP and CCE superfamilies in the recently sequenced M. occidentalis genome. The gene count represents a reduction of 35% compared to T. urticae. The distribution of genes in the GST and CCE superfamilies in M. occidentalis differs significantly from those of insects and resembles that of T. urticae. Specifically, we report the presence of the Mu class GSTs, and the J’ and J” clade CCEs that, within the Arthropoda, appear unique to Acari. Interestingly, the majority of CCEs in the J’ and J” clades contain a catalytic triad, suggesting that they are catalytically active. They likely represent two Acari-specific CCE clades that may participate in detoxification of xenobiotics. The current study of genes in these superfamilies provides preliminary insights into the potential molecular components that may be involved in pesticide metabolism as well as hormonal/chemosensory processes in the agriculturally important M. occidentalis. PMID:27467523

  3. THE EFFECT OF IONIZING RADIATION ON ACETYLCHOLINE METABOLISM IN MACACA- RHESUS MONKEYS

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Demin, N.N.; Korneeva, N.V.; Shaternikov, V.A.

    1961-11-01

    In macaca-rhesus monkeys the normal content of free acetylcholine in the mucosa of the small intestine was higher, as it was in brain and liver, than bound acetyl choline. The total cholinesterase activity and, particularly, the activity of acetylcholinesterase and non-specific cholinesterase in control monkeys is highest in brain, followed by intestinal mucosa and liver. One to three days after gamma -irradiation of the monkey at a dose of 600 r the amount of free and bound acetylcholine in the mucosa of the small intestine increased, while it decreased in liver. The total cholinesterase activity in the mucosa of themore » small intestine during this period increased, in general because of the increase in the activity of non-specific cholinesterase. In the liver the increase in total cholinesterase activity also occurred because of an increase in non-specific cholinesterase activity, but was less clear-cut and occurred later (the third day after irradiation). In animals irradiated 2 to 3 years before the investigation, an increased concentration of free acetylcholine in brain, liver, and mucosa of the small intestine was noted; but there were no ehanges in bound acetylcholine. The total cholinesterase activity increased in liver as a result of acetyl cholinesterase increase and non-specific enzymes, and in mucosa of the small intestine only as a result of acetylcholinesterase activity. In brain the total cholinesterase activity decreased as a consequence of a decrease in acetylcholinesterase activity. (auth)« less

  4. Endochondral Ossification Is Accelerated in Cholinesterase-Deficient Mice and in Avian Mesenchymal Micromass Cultures

    PubMed Central

    Spieker, Janine; Mudersbach, Thomas; Vogel-Höpker, Astrid; Layer, Paul G.

    2017-01-01

    Most components of the cholinergic system are detected in skeletogenic cell types in vitro, yet the function of this system in skeletogenesis remains unclear. Here, we analyzed endochondral ossification in mutant murine fetuses, in which genes of the rate-limiting cholinergic enzymes acetyl- (AChE), or butyrylcholinesterase (BChE), or both were deleted (called here A-B+, A+B-, A-B-, respectively). In all mutant embryos bone growth and cartilage remodeling into mineralizing bone were accelerated, as revealed by Alcian blue (A-blu) and Alizarin red (A-red) staining. In A+B- and A-B- onset of mineralization was observed before E13.5, about 2 days earlier than in wild type and A-B+ mice. In all mutants between E18.5 to birth A-blu staining disappeared from epiphyses prematurely. Instead, A-blu+ cells were dislocated into diaphyses, most pronounced so in A-B- mutants, indicating additive effects of both missing ChEs in A-B- mutant mice. The remodeling effects were supported by in situ hybridization (ISH) experiments performed on cryosections from A-B- mice, in which Ihh, Runx2, MMP-13, ALP, Col-II and Col-X were considerably decreased, or had disappeared between E18.5 and P0. With a second approach, we applied an improved in vitro micromass model from chicken limb buds that allowed histological distinction between areas of cartilage, apoptosis and mineralization. When treated with the AChE inhibitor BW284c51, or with nicotine, there was decrease in cartilage and accelerated mineralization, suggesting that these effects were mediated through nicotinic receptors (α7-nAChR). We conclude that due to absence of either one or both cholinesterases in KO mice, or inhibition of AChE in chicken micromass cultures, there is increase in cholinergic signalling, which leads to increased chondroblast production and premature mineralization, at the expense of incomplete chondrogenic differentiation. This emphasizes the importance of cholinergic signalling in cartilage and bone

  5. Treatment with endotracheal therapeutics after sarin microinstillation inhalation exposure increases blood cholinesterase levels in guinea pigs.

    PubMed

    Che, Magnus M; Song, Jian; Oguntayo, Samuel; Doctor, Bhupendra P; Rezk, Peter; Perkins, Michael W; Sciuto, Alfred M; Nambiar, Madhusoodana P

    2012-05-01

    Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities were measured in the blood and tissues of animals that are treated with a number of endotracheally aerosolized therapeutics for protection against inhalation toxicity to sarin. Therapeutics included, aerosolized atropine methyl bromide (AMB), scopolamine or combination of AMB with salbutamol, sphingosine 1-phosphate, keratinocyte growth factor, adenosine A1 receptor antisense oligonucleotide (EPI2010), 2,3-diacetyloxybenzoic acid (2,3 DABA), oxycyte, and survanta. Guinea pigs exposed to 677.4 mg/m(3) or 846.5 mg/m(3) (1.2 LCt(50)) sarin for 4 min using a microinstillation inhalation exposure technique and treated 1 min later with the aerosolized therapeutics. Treatment with all therapeutics significantly increased the survival rate with no convulsions throughout the 24 h study period. Blood AChE activity determined using acetylthiocholine as substrate showed 20% activity remaining in sarin-exposed animals compare to controls. In aerosolized AMB and scopolamine-treated animals the remaining AChE activity was significantly higher (45-60%) compared to sarin-exposed animals (p < 0.05). Similarly, treatment with all the combination therapeutics resulted in significant increase in blood AChE activity in comparison to sarin-exposed animals although the increases varied between treatments (p < 0.05). BChE activity was increased after treatment with aerosolized therapeutics but was lesser in magnitude compared to AChE activity changes. Various tissues showed elevated AChE activity after therapeutic treatment of sarin-exposed animals. Increased AChE and BChE activities in animals treated with nasal therapeutics suggest that enhanced breathing and reduced respiratory toxicity/lung injury possibly contribute to rapid normalization of chemical warfare nerve agent inhibited cholinesterases.

  6. Diverse inhibitory actions of quaternary ammonium cholinesterase inhibitors on Torpedo nicotinic ACh receptors transplanted to Xenopus oocytes

    PubMed Central

    Olivera-Bravo, Silvia; Ivorra, Isabel; Morales, Andrés

    2007-01-01

    Background and purpose: This work was aimed at comparing and analysing the effects and mechanisms of action of the quaternary ammonium cholinesterase inhibitors (QChEIs) BW284c51, decamethonium and edrophonium, on nicotinic ACh receptor (nAChR) function. Experimental approach: nAChRs purified from Torpedo electroplax were transplanted to oocytes and currents elicited by ACh (IACh) either alone or in presence of these QChEIs were recorded. Key results: None of the QChEIs, by itself, elicited changes in membrane conductance; however, when co-applied with ACh, all of them decreased IACh in a concentration-dependent way. The mechanisms of nAChR inhibition were different for these QChEIs. BW284c51 blockade was non-competitive and voltage-dependent, although it also affected the nH of the dose-response curve. By contrast, decamethonium and edrophonium inhibition, at –60 mV, was apparently competitive and did not modify either desensitisation or nH. Decamethonium effects were voltage-independent and washed out slowly after its removal; by contrast, edrophonium blockade had strong voltage dependence and its effects disappeared quickly after its withdrawal. Analysis of the voltage-dependent blockade indicated that BW284c51 bound to a shallow site into the channel pore, whereas edrophonium bound to a deeper locus. Accordingly, additive inhibitory effects on IACh were found among any pairs of these QChEIs. Conclusions and implications: The tested QChEIs bound to the nAChR at several and different loci, which might account for their complex inhibitory behaviour, acting both as allosteric effectors and, in the case of BW284c51 and edrophonium, as open channel blockers. PMID:17572698

  7. Comparison of several oximes on reactivation of soman-inhibited blood, brain and tissue cholinesterase activity in rats

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Shih, T.M.

    1993-12-31

    The ability of three oximes, HI-6, MMB-4 and ICD-467, to reactivate cholinesterase (ChE) inhibited by the organophosphorus compound soman was compared in blood (plasma and erythrocytes), brain regions (including spinal cord) and peripheral tissues of rats. Animals were intoxicated with soman (100 ttg/kg. SC; equivalent to 0.9 x LDs0 dose) and treated 1 min later with one of these oximes (100 or 200 ttmo1/kg, IM). Toxic sign scores and total tissue ChE activities were determined 30 min later. Soman markedly inhibited ChE activity in blood (93 - 96%), brain regions (ranging from 78% to 95%), and all peripheral tissues (rangingmore » from 48.9% to 99.8%) except liver (11.9%). In blood, treatment with HI-6 or ICD-467 resulted in significant reactivation of soman-inhibited ChE. in contrast, MMB-4 was completely ineffective. HI-6 and ICD-467 were equally effective at the high dose. At the low dose ICD-467 treatment resulted in significantly higher plasma ChE than Hl-6 treatment, whereas HI-6 treatment resulted in higher erythrocyte ChE than ICD-467 treatment. However, none of these three oximesreactivated or protected soman-inhibited ChE in the brain. In all peripheral tissues (except liver) studied, MMB-4 was not effective. 111-6 reactivated soman-inhibited ChE in all tis- sues except lung, heart, and skeletal muscle. ICD-467 was highly effective in reactivating ChE in all tissues and afforded a complete recovery of ChE to control levels in Intercostal muscle and salivary gland. Oxime treatments did not modify the toxic scores produced by soman.« less

  8. Inhibition pathways of the potent organophosphate CBDP with cholinesterases revealed by X-ray crystallographic snapshots and mass spectrometry.

    PubMed

    Carletti, Eugénie; Colletier, Jacques-Philippe; Schopfer, Lawrence M; Santoni, Gianluca; Masson, Patrick; Lockridge, Oksana; Nachon, Florian; Weik, Martin

    2013-02-18

    Tri-o-cresyl-phosphate (TOCP) is a common additive in jet engine lubricants and hydraulic fluids suspected to have a role in aerotoxic syndrome in humans. TOCP is metabolized to cresyl saligenin phosphate (CBDP), a potent irreversible inhibitor of butyrylcholinesterase (BChE), a natural bioscavenger present in the bloodstream, and acetylcholinesterase (AChE), the off-switch at cholinergic synapses. Mechanistic details of cholinesterase (ChE) inhibition have, however, remained elusive. Also, the inhibition of AChE by CBDP is unexpected, from a structural standpoint, i.e., considering the narrowness of AChE active site and the bulkiness of CBDP. In the following, we report on kinetic X-ray crystallography experiments that provided 2.7-3.3 Å snapshots of the reaction of CBDP with mouse AChE and human BChE. The series of crystallographic snapshots reveals that AChE and BChE react with the opposite enantiomers and that an induced-fit rearrangement of Phe297 enlarges the active site of AChE upon CBDP binding. Mass spectrometry analysis of aging in either H(2)(16)O or H(2)(18)O furthermore allowed us to identify the inhibition steps, in which water molecules are involved, thus providing insights into the mechanistic details of inhibition. X-ray crystallography and mass spectrometry show the formation of an aged end product formed in both AChE and BChE that cannot be reactivated by current oxime-based therapeutics. Our study thus shows that only prophylactic and symptomatic treatments are viable to counter the inhibition of AChE and BChE by CBDP.

  9. Synthesis of new N-benzylpiperidine derivatives as cholinesterase inhibitors with β-amyloid anti-aggregation properties and beneficial effects on memory in vivo.

    PubMed

    Więckowska, Anna; Więckowski, Krzysztof; Bajda, Marek; Brus, Boris; Sałat, Kinga; Czerwińska, Paulina; Gobec, Stanislav; Filipek, Barbara; Malawska, Barbara

    2015-05-15

    Due to the complex nature of Alzheimer's disease, multi-target-directed ligand approaches are one of the most promising strategies in the search for effective treatments. Acetylcholinesterase, butyrylcholinesterase and β-amyloid are the predominant biological targets in the search for new anti-Alzheimer's agents. Our aim was to combine both anticholinesterase and β-amyloid anti-aggregation activities in one molecule, and to determine the therapeutic potential in vivo. We designed and synthesized 28 new compounds as derivatives of donepezil that contain the N-benzylpiperidine moiety combined with the phthalimide or indole moieties. Most of these test compounds showed micromolar activities against cholinesterases and aggregation of β-amyloid, combined with positive results in blood-brain barrier permeability assays. The most promising compound 23 (2-(8-(1-(3-chlorobenzyl)piperidin-4-ylamino)octyl)isoindoline-1,3-dione) is an inhibitor of butyrylcholinesterase (IC50=0.72 μM) that has β-amyloid anti-aggregation activity (72.5% inhibition at 10 μM) and can cross the blood-brain barrier. Moreover, in an animal model of memory impairment induced by scopolamine, the activity of 23 was comparable to that of donepezil. The selected compound 23 is an excellent lead structure in the further search for new anti-Alzheimer's agents. Copyright © 2015 Elsevier Ltd. All rights reserved.

  10. Potential anti-cholinesterase and β-site amyloid precursor protein cleaving enzyme 1 inhibitory activities of cornuside and gallotannins from Cornus officinalis fruits.

    PubMed

    Bhakta, Himanshu Kumar; Park, Chan Hum; Yokozawa, Takako; Tanaka, Takashi; Jung, Hyun Ah; Choi, Jae Sue

    2017-07-01

    Cholinesterase (ChE) and β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors are promising agents for the treatment of Alzheimer's disease (AD). In the present study, we examined the inhibitory activity of seven compounds isolated from the fruits of Cornus officinalis, cornuside, polymeric proanthocyanidins, 1,2,3-tri-O-galloyl-β-D-glucose, 1,2,3,6-tetra-O-galloyl-β-D-glucose, tellimagrandin I, tellimagrandin II, and isoterchebin, against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and BACE1. All of the compounds displayed concentration-dependent in vitro inhibitory activity toward the ChEs and BACE1. Among them, tellimagrandin II exhibited the best inhibitory activity toward ChEs, whereas the best BACE1 inhibitor was 1,2,3,6-tetra-O-galloyl-β-D-glucose. Isoterchebin and polymeric proanthocyanidins were also significant ChE inhibitors. The kinetic and docking studies demonstrated that all compounds interacted with both the catalytic active sites and the peripheral anionic sites of the ChEs and BACE1. Tellimagrandin II, isoterchebin, and the polymeric proanthocyanidins exhibited concentration-dependent inhibition of peroxynitrite-mediated protein tyrosine nitration. In conclusion, we identified significant ChE and BACE1 inhibitors from Corni Fructus that could have value as new multi-targeted compounds for anti-AD agents.

  11. New antimuscarinic agents for improved treatment of poisoning by cholinesterase inhibitors. Annual progress report No. 1, 1 November 1982-31 October 1983

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Stubbins, J.F.

    The object of this project is to find a more effective antimuscarinic agent than atropine for use as an antidote for poisoning by organophosphate cholinesterase inhibitors. To start this search, 22 structurally-diverse antimuscarinic agents have been selected for initial testing. These compounds are to be evaluated for peripheral and central antimuscarinic activity in a variety of in vitro and in vivo tests in addition to determining their effectiveness as antidotes (in combination with an oxime reactivator) for poisoning by soman. Fifteen of the compounds have now been evaluated for ability to block acetylcholine-induced contractions in guinea pig intestinal smooth musclemore » compared to atropine. Ability to displace radiolabeled quinuclidinyl benzilate from muscarinic receptors of mouse brain homogenate has been determined for atropine, scopolamine and 19 of the compounds. Several of these compounds have a relatively stronger affinity for brain than for intestinal muscarinic receptors. Atropine, scopolamine and 12 of the compounds have also been examined as inhibitors of tremors induced by oxotremorine in mice. Two of the compounds are much more potent than atropine. None of the compounds have been tested as yet as antidotes for soman poisoning. Samples of the test compounds are being sent to the Medical Research Institute of Chemical Defense for evaluation of this property.« less

  12. Effects in vivo of iohexol and diatrizoate on human plasma acetyl- and butyryl-cholinesterase activity.

    PubMed

    Mironidou, M; Katsimba, D; Kokkas, B; Kaitartzis, C; Karamanos, G; Christopoulos, S

    2001-03-01

    The aim of this study was to evaluate the effects of two iodinate contrast agents (CA), iohexol and diatrizoate, on human plasma acetyl-(AC) and butyrylcholinesterase(BC) activity. Forty-eight patients (24 males and 24 females) scheduled for intravenous pyelography were randomly divided into four groups of 6 males and 6 females each, receiving as CA, respectively: iohexol (Omnipaque, Schering) 0.6 ml/kg body weight (G1); iohexol 1.2 mg/kg (G2); sodium and meglumine diatrizoate 58% (Urografin, Schering) 0.6 ml/kg (G3); sodium and meglumine diatrizoate 58% 1.2 ml/kg (G4). Blood samples were taken before and 5, 10, and 20 min after the injection. Enzymatic activity of AC and BC were measured by spectrophotometry. Plasma concentration of K, Na, Ca, and Mg was measured in all blood samples; blood pressure and plasma pH were measured after each sample collection. Statistical analysis was performed by Student's test. In G1 a reversible decrease of AC (12.9%) and BC (8.2%) plasma activity was observed at 10 min. In G2 a progressive decrease of AC (13.9%) and BC (18.4%) plasma activity was observed with a maximum at 20 min. In G3 a modest reversible decrease of BC plasma activity (5.4%) was observed. In G4 a modest progressive decrease of AC (7.3%) and BC (6.5%) plasma activities was observed. In all cases, AC and BC plasma activities remained within the normal range of values. Plasma concentration of K, Na, Ca, and Mg, as well as pH and systolic and diastolic pressure, did not show any change. No adverse effects was observed in our patients. Iohexol and diatrizoate induce in vivo a significant decrease of AC and BC plasma activities. The decrease is more pronounced for iohexol, a non ionic CA, which has a lower pharmacotoxicity than diatrizoate and adverse effects rate. No inference can be drawn about the relationship between plasma cholinesterase activity and adverse effects.

  13. Natural Detoxification Capacity to Inactivate Nerve Agents Sarin and VX in the Rat Blood.

    PubMed

    Bajgar, Jiří; Cabal, Jiří; Kassa, Jiří; Pavlík, Michal

    2015-01-01

    The method of continual determination of the rat blood cholinesterase activity was developed to study the changes of the blood cholinesterases following different intervetions. The aim of this study is registration of cholinesterase activity in the rat blood and its changes to demonstrate detoxification capacity of rats to inactivate sarin or VX in vivo. The groups of female rats were premedicated (ketamine and xylazine) and cannulated to a. femoralis. Continual blood sampling (0.02 ml/min) and monitoring of the circulating blood cholinesterase activity were performed. Normal activity was monitored 1-2 min and then the nerve agent was administered i.m. (2×LD50). Using different time intervals of the leg compression and relaxation following the agent injection, cholinesterase activity was monitored and according to the inhibition obtained, detoxification capacity was assessed. Administration of sarin to the leg, then 1 and 5 min compression and 20 min later relaxation showed that further inhibition in the blood was not observed. On the other hand, VX was able to inhibit blood cholinesterases after this intervention. The results demonstrated that sarin can be naturally detoxified on the contrary to VX. Described method can be used as model for other studies dealing with changes of cholinesterases in the blood following different factors.

  14. Preparation and in vitro screening of symmetrical bis-isoquinolinium cholinesterase inhibitors bearing various connecting linkage--implications for early Myasthenia gravis treatment.

    PubMed

    Musilek, Kamil; Komloova, Marketa; Holas, Ondrej; Hrabinova, Martina; Pohanka, Miroslav; Dohnal, Vlastimil; Nachon, Florian; Dolezal, Martin; Kuca, Kamil

    2011-02-01

    Inhibitors of acetylcholinesterase are compounds widely used in the treatment of various diseases, such as Alzheimer's disease, glaucoma and Myasthenia gravis (MG). Compounds used in the therapy of MG posses a positive charge in the molecule to ensure peripheral effect of action and minimal blood-brain barrier penetration. The most prescribed carbamate inhibitors are however known for many severe side effects related to the carbamylation of AChE. This paper describes preparation and in vitro evaluation of 20 newly prepared bis-isoquinolinium inhibitors of potential concern for MG. The newly prepared compounds were evaluated in vitro on human recombinant AChE and human plasmatic butyrylcholinesterase (BChE). Their inhibitory ability was expressed as IC50 and compared to chosen standards ambenonium dichloride, edrophonium chloride, BW284c51 and ethopropazine hydrochloride. Three novel compounds presented promising inhibition (in nM range) of both enzymes in vitro better or similar to edrophonium and BW284c51, but worse to ambenonium. The novel inhibitors did not present higher selectivity toward AChE or BChE. The kinetic assay confirmed non-competitive inhibition of hAChE by two selected promising novel compounds. Two newly prepared compounds were also chosen for docking studies that confirmed apparent π-π or π-cationic interactions aside the cholinesterases catalytic sites. The SAR findings were discussed. Copyright © 2010 Elsevier Masson SAS. All rights reserved.

  15. Effects of biological and technical factors on brain and muscle cholinesterases in Nile tilapia, Oreochromis niloticus: implications for biomonitoring neurotoxic contaminations.

    PubMed

    Pathiratne, A; Chandrasekera, L W H U; De Seram, P K C

    2008-02-01

    Influence of body length, body weight, gender, sexual maturity, and tissue storage on brain and muscle cholinesterases (ChE) in Nile tilapia was evaluated considering its potential use in biomonitoring neurotoxic contaminations in tropical environments. Results show that ChE activities in both tissues decreased significantly with increased total length (4-24.5 cm) or body weight (1-186 g) of the fish and the relationships were curvilinear. Comparisons of the slopes and elevations of the regression lines of the logarithmic ChE and body size relationships of males with those of females indicated that gender had no significant effect on the body size-specific ChE activities. Response of the ChE of sexually mature males to chlorpyrifos exposure was similar to that of females. Gonadal maturity stage of this fish does not seem to influence ChE activities. Storage of tissues at -80 degrees C for 28 days had no significant effect on ChE activities in the control fish and the fish exposed to carbofuran. However, a partial reactivation of brain ChE activities was observed in the fish exposed to carbosulfan after 28 days of storage. The results emphasize the importance of consideration of body size of the fish and storage time of the tissues in order to formulate accurate conclusions about the neurotoxic chemical exposure when ChE of the fish is used in biomonitoring programs.

  16. Cholinesterase-inhibitory effect and in silico analysis of alkaloids from bulbs of Hieronymiella species.

    PubMed

    Ortiz, Javier E; Garro, Adriana; Pigni, Natalia B; Agüero, María Belén; Roitman, German; Slanis, Alberto; Enriz, Ricardo D; Feresin, Gabriela E; Bastida, Jaume; Tapia, Alejandro

    2018-01-15

    In Argentina, the Amaryllidaceae family (59 species) comprises a wide variety of genera, only a few species have been investigated as a potential source of cholinesterases inhibitors to treat Alzheimer disease (AD). To study the acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities of the basic dichloromethane extracts (E) from Hieronymiella aurea, H. caletensis, H. clidanthoides, H. marginata, and H. speciosa species, as well as the isolated compounds from these plant extracts. AChE and BChE inhibitory activities were evaluated with the Ellman's spectrophotometric method. The alkaloids composition from the E was obtained by gas chromatography-mass spectrometry (GC-MS). The E were successively chromatographed on a silica gel column and permeated on Sephadex LH-20 column to afford the main alkaloids identified by means of spectroscopic data. Additionally, an in silico study was carried out. Nine known alkaloids were isolated from the E of five Hieronymiella species. Galanthamine was identified in all the species by GC-MS standing out H. caletensis with a relative abundance of 9.79% of the total ion current. Strong AChE (IC 50  = 1.84 - 15.40 µg/ml) and moderate BChE (IC50 = 23.74 - 136.40 µg/ml) inhibitory activities were displayed by the extracts. Among the isolated alkaloids, only sanguinine and chlidanthine (galanthamine-type alkaloids) demonstrated inhibitory activity toward both enzymes. The QTAIM study suggests that sanguinine has the strongest affinity towards AChE, attributed to an additional interaction with Ser200 as well as stronger molecular interactions Glu199 and His440.These results allowed us to differentiate the molecular behavior in the active site among alkaloids possessing different in vitro inhibitory activities. Hieronymiella species growing in Argentina represent a rich and widespread source of galanthamine and others AChE and BChE inhibitors alkaloids. Additionally, the new trend towards the use of

  17. A Pharmacokinetic Study of the Effects of Stress and Exercise on Chemical Exposure

    DTIC Science & Technology

    2001-03-20

    Organophosphates such as diazinon and malathion are considered cholinesterase inhibitors, while carbamates such as physostigmine and pyridostigmine...bromide (PB) are considered reversible cholinesterase inhibitors. The possible Gulf War exposures to organophosphates such as diazinon and malathion...indicate that the physiological and protective effects of carbamates such as PB may depend on a narrow range of cholinesterase inhibition. Blood

  18. Long term exposure to low dose neurotoxic pesticides affects hatching, viability and cholinesterase activity of Artemia sp.

    PubMed

    Gambardella, Chiara; Nichino, Daniela; Iacometti, Camillo; Ferrando, Sara; Falugi, Carla; Faimali, Marco

    2018-03-01

    The brine shrimp Artemia was used as a model organism to test toxicity of several neuroactive pesticides (chlorpyrifos (CLP), chlorpyrifos oxon (CLP ox), diazinon (DZN), carbaryl (CBR)) following exposure to far below than lethal doses. Cysts were exposed to the pesticides in order to test a scenario similar to actual coastal environment contamination, by analyzing different responses. Cysts were rehydrated in water containing the pesticides at concentrations ranging from 10 -11 to 10 -5  M, for 72, 96 and 192 h, respectively. For these exposure times, morpho-functional and biochemical parameters, such as hatching speed and viability were investigated in the larvae together with cholinesterase (ChE) activity quantification and histochemical localization. Finally, ChE inhibition was also compared with conventional selective ChE inhibitors. Results showed that CLP ox and CBR caused a significant dose-dependent decrease in hatching speed, followed by high percentages of larval death, while CLP and DZN were responsible for irregular hatching patterns. In addition, the pesticides mostly caused larval death some days post-hatching, whereas this effect was negligible for the specific ChE inhibitors, suggesting that part of pesticide toxicity may be due to molecules other than the primary target. ChE activity was observed in the protocerebrum lobes, linked to the development of pair eyes. Such activity was inhibited in larvae exposed to all pesticides. When compared to conventional selective inhibitors of ChE activities, this inhibition demonstrated that the selected pesticides mainly affect acetylcholinesterase and, to a lesser extent, pseudocholinesterases. In conclusion, the brine shrimp is a good model to test the environmental toxicity of long term exposure to cholinergic pesticides, since changes in hatching speed, viability and ChE activity were observed. Copyright © 2018 Elsevier B.V. All rights reserved.

  19. Oxotremorine-induced hypothermia as a method for evaluating long-term neuronal changes following poisoning by cholinesterase inhibitors in rats.

    PubMed

    Grauer, E; Levy, A

    2007-12-05

    Severe poisoning by inhibitors of cholinesterase (ChE) enzymes is often associated with prolonged central or peripheral neuronal damage. Oxotremorine is a cholinergic agonist known to induce acute hypothermia. Central and peripheral cholinergic signaling is involved in the induction of hypothermia as well as in its recovery. These processes were used in the present study to reveal prolonged neuronal abnormalities in poisoned rats, using oxotremorine with and without concomitant administration of the peripheral muscarinic antagonist methyl scopolamine. In non-poisoned naïve rats, the hypothermic effect of oxotremorine appeared faster while its recovery was delayed following co-administration of methyl scopolamine, suggesting predominantly peripheral processes in counteracting the hypothermia. One month after exposure to approximately 1LD(50) of the carbamates aldicarb and oxamyl, the hypothermic effect of oxotremorine was similar to that found in saline-treated control group. However, the effect of methyl scopolamine on the recovery process was significantly diminished, indicating that the impaired cholinergic mechanisms were predominantly peripheral. In contrast, 1 month following organophosphate (OP) poisoning by the nerve agents sarin and VX, oxotremorine-induced hypothermia was reduced, indicating mainly impaired central cholinergic mechanisms. The development of severe convulsions during nerve agent poisoning may explain the central neuronal damage in OP-poisoned rats, displayed as reduced hypothermia. As convulsions were not part of the poisoning symptoms with the carbamates tested, their long-term damage was displayed at the recovery stage. This method might be used as a relatively simple means for detecting differential long-term central and peripheral cholinergic injuries, long after toxicity signs have receded.

  20. Differences between male and female rhesus monkey erythrocyte acetylcholinesterase and plasma cholinesterase activity before and after exposure to sarin

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Woodard, C.L.; Calamaio, C.A.; Kaminskis, A.

    The female rhesus monkey has a menstrual cycle like the human. Additionally, several differences in enzyme levels between males and females and in the female during the menstrual cycle are present. Therefore we quantitated plasma cholinesterase (ChE/BuChE) and erythrocyte (RBC) acetylcholinesterase (AChE) activity before and after exposure to sarin (GB)(1 5 ug/kg, iv; a 0.75 LD50), in male and female rhesus (Macaca mulatta) monkeys. Twenty-eight-day preexposure baseline plasma ChE and RBC AChE values for six male and six female rhesus monkeys were compared for intra-animal, within sex and between sex differences. After these baseline values were obtained, the organophosphorus (OP)more » compound/Isopropyl methylphosphono-fluoridate (GB) was administered to atropinized monkeys to determine if there was a significant in vivo difference between the sexes in their response to this intoxication in regard to the rate of BuChE /AChE inhibition, pyridine-2-aldoxime methyl chloride (2-PAM) reactivation of the phosphonylated BuChE and the rate of aging of the phosphonylated:BuChE/AChE. In the pre-exposure portion of the protocol; the intra-animal and intra-group BuChE/AChE variations were found to be minimal; but there were significant differences between the male and female monkeys in both plasma BuChE and RBC AChE levels; although probably clinically insignificant in respect to an OP intoxication. No significant cyclic fluctuations were seen during the 28-day study in either sex.« less

  1. Time course of cholinesterase activity in plasma, brain and muscle of rat pretreated with physostigmine, and then soman

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Giacobini, E.; Boyer, A.; Somani, S.M.

    1986-03-05

    Time course of /sup 3/H-physostigmine (Phy) concentration and cholinesterase (ChE) activity in plasma and tissues was studied in rats pretreated with Phy and then soman. Rats were dosed with Phy (100 ..mu..g/kg, i.v.), 5 or 15 min prior to soman (105 ..mu..g/kg, 1.5 LD/sub 50/, s.c.) treatment and were sacrificed at various times; Phys conc. and ChE activity were determined. BuChE activity in plasma was 5% of control from 7-30 min after Phy i.v. pretreatment and soman or soman alone treatment. Plasma Phy conc. steadily declined (32.6 ng/ml at 7 min) to 15 ng/ml at 30 min. ChE activity inmore » muscle was 60-50% of control for Phy pretreated but soman alone gave 85-72% activity from 2-30 min. Brain ChE activity was about 5% of control within 2 min after soman treatment; however, with Phy pretreatment, the activity was about 52% at 7 min, 40% at 22 min, which recovered to 45% of control at 35 min, indicating that Phy protected brain ChE. Brain Phy conc. steadily declined (58.6 ng/g at 7 min) to 11.7 ng/g at 30 min. However, pretreatment of rat with a higher dose of Phy and then soman showed BuChE in plasma and ChE in brain and muscle to be about 25, 35 and 51%, in comparison to about 5% in plasma and brain with soman alone treatment, indicating higher protection of ChE enzyme with higher conc. of Phy in plasma and brain.« less

  2. Copper (II) and zinc (II) complexes with flavanone derivatives: Identification of potential cholinesterase inhibitors by on-flow assays.

    PubMed

    Sarria, André Lucio Franceschini; Vilela, Adriana Ferreira Lopes; Frugeri, Bárbara Mammana; Fernandes, João Batista; Carlos, Rose Maria; da Silva, Maria Fátima das Graças Fernandes; Cass, Quezia Bezerra; Cardoso, Carmen Lúcia

    2016-11-01

    Metal chelates strongly influence the nature and magnitude of pharmacological activities in flavonoids. In recent years, studies have shown that a promising class of flavanone-metal ion complexes can act as selective cholinesterase inhibitors (ChEIs), which has led our group to synthesize a new series of flavanone derivatives (hesperidin, hesperetin, naringin, and naringenin) complexed to either copper (II) or zinc (II) and to evaluate their potential use as selective ChEIs. Most of the synthesized complexes exhibited greater inhibitory activity against acetylcholinesterase (AChE) than against butyrylcholinesterase (BChE). Nine of these complexes constituted potent, reversible, and selective ChEIs with inhibitory potency (IC 50 ) and inhibitory constant (K i ) ranging from 0.02 to 4.5μM. Copper complexes with flavanone-bipyridine derivatives afforded the best inhibitory activity against AChE and BChE. The complex Cu(naringin)(2,2'-bipyridine) (11) gave IC 50 and K i values of 0.012±0.002 and 0.07±0.01μM for huAChE, respectively, which were lower than the inhibitory values obtained for standard galanthamine (IC 50 =206±30.0 and K i =126±18.0μM). Evaluation of the inhibitory activity of this complex against butyrylcholinesterase from human serum (huBChE) gave IC 50 and K i values of 8.0±1.4 and 2.0±0.1μM, respectively. A Liquid Chromatography-Immobilized Capillary Enzyme Reactor by UV detection (LC-ICER-UV) assay allowed us to determine the IC 50 and K i values and the type of mechanism for the best inhibitors. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Serum cholinesterase polymorphism (CHE1 and CHE2 loci) among several Indian groups from Amazon region of Brazil, and segregation of the C5 variant in families.

    PubMed

    Guerreiro, J F; Santos, S E; Aguiar, G F

    1989-04-01

    Eight Indian tribes from the Amazon region of Brazil (Araweté, Arara, Yamamadi, Kararaô, Karitiana, Waiampi, Surui and Cinta Larga) were studied for the distribution of the atypical and C5 variants of serum cholinesterase. None of them presented the CHE1*A allele, but the C5 variant was found in the Araweté (20.4%), Kararaô (15.6%), Karitiana (50.5%), Surui (12.3%) and Cinta Larga (19.6%) tribes. The frequency of the C5+ phenotype in the Karitiana is the highest reported thus far in human populations. Segregation studies considering the C5 variant were made among the Karitiana, and also among the Urubu-Kaapor and Munduruku tribes previously studied by Guerreiro et al [1987a, 1987b]. Most of the data were in agreement with the genetic hypothesis, but they also revealed a significant lack of the C5+ phenotype in offspring from C5+ X C5+ matings, as well as the occurrence of two C5+ children from C5- X C5- unions, in the Urubu-Kaapor tribe.

  4. One Hundred Eighty Day Subchronic Oral Toxicity Study of Pyridostigmine Bromide in Rats. Volume 1

    DTIC Science & Technology

    1990-06-01

    has proposed a treatment regimen incorporating prophylaxis with a reversible cholinesterase inhibitor and, following nerve agent exposure, antidotal...would accomplish two goals: the oxime would abate the inhibition induced by the reversible cholinesterase inhibitor prophylaxis, and the atropine will...cholinesterase inhibitor as the pretreatment component of a therapeutic regimen that would include antidotal therapy with 2-PAM chloride and atropine. A

  5. Protective propensity of bacoside A and bromelain on renal cholinesterases, γ-Aminobutyric acid and serotonin level of Mus musculus intoxicated with dichlorvos.

    PubMed

    Agarwal, Sonam; Chaudhary, Bharti; Bist, Renu

    2017-01-05

    Current study established a protective action of bacoside A and bromelain against the toxic effects of dichlorvos in kidneys of mice. Experimental design included five groups. The first group was control. Mice of groups II, III and IV were administered doses of dichlorvos, bromelain and bacoside A respectively. In group V, mice were treated with both the antioxidants (bacoside A and bromelain) and dichlorvos. After 21 days of exposure of different doses, levels of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), γ-aminobutyric acid (GABA) and serotonin were measured in renal tissues. Dichlorvos significantly reduced the kidney AChE (p < 0.001), BChE (p < 0.01) and GABA level (p < 0.01) compared to control. A simultaneous significant elevation in the serotonin level (p < 0.01) was recorded after dichlorvos exposure. Concomitant exposure of bacoside A and bromelain followed by dichlorvos treatment in group V not only restored, but increased the renal cholinesterases and GABA level. Meanwhile, a significant decline in serotonin level (p < 0.001) was revealed, compared to dichlorvos exposed mice. Bacoside A and bromelain occupy a tremendous antioxidant action in the mice kidneys and a combination of the same ameliorates the renal toxicity induced by dichlorvos. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  6. Age-Related Decline in Brain and Hepatic Clearance of Amyloid-Beta is Rectified by the Cholinesterase Inhibitors Donepezil and Rivastigmine in Rats.

    PubMed

    Mohamed, Loqman A; Qosa, Hisham; Kaddoumi, Amal

    2015-05-20

    In Alzheimer's disease (AD), accumulation of brain amyloid-β (Aβ) depends on imbalance between production and clearance of Aβ. Several pathways for Aβ clearance have been reported including transport across the blood-brain barrier (BBB) and hepatic clearance. The incidence of AD increases with age and failure of Aβ clearance correlates with AD. The cholinesterase inhibitors (ChEIs) donepezil and rivastigmine are used to ease the symptoms of dementia associated with AD. Besides, both drugs have been reported to provide neuroprotective and disease-modifying effects. Here, we investigated the effect of ChEIs on age-related reduced Aβ clearance. Findings from in vitro and in vivo studies demonstrated donepezil and rivastigmine to enhance (125)I-Aβ40 clearance. Also, the increase in brain and hepatic clearance of (125)I-Aβ40 was more pronounced in aged compared to young rats, and was associated with significant reduction in brain Aβ endogenous levels determined by ELISA. Furthermore, the enhanced clearance was concomitant with up-regulation in the expression of Aβ major transport proteins P-glycoprotein and LRP1. Collectively, our findings that donepezil and rivastigmine enhance Aβ clearance across the BBB and liver are novel and introduce an additional mechanism by which both drugs could affect AD pathology. Thus, optimizing their clinical use could help future drug development by providing new drug targets and possible mechanisms involved in AD pathology.

  7. Neuroprotective Effects and Mechanisms of Action of Multifunctional Agents Targeting Free Radicals, Monoamine Oxidase B and Cholinesterase in Parkinson's Disease Model.

    PubMed

    Liu, Zheng; Cai, Wei; Lang, Ming; Yan, Ruizuo; Li, Zhenshen; Zhang, Gaoxiao; Yu, Pei; Wang, Yuqiang; Sun, Yewei; Zhang, Zaijun

    2017-04-01

    Parkinson's disease (PD) is a complex neurodegenerative disorder with multifactorial pathologies, including progressive loss of dopaminergic (DA) neurons, oxidative stress, mitochondrial dysfunction, and increased monoamine oxidase (MAO) enzyme activity. There are currently only a few agents approved to ameliorate the symptoms of PD; however, no agent is able to reverse the progression of the disease. Due to the multifactorial pathologies, it is necessary to develop multifunctional agents that can affect more than one target involved in the disease pathology. We have designed and synthesized a series of new multifunctional anti-Parkinson's compounds which can protect cerebral granular neurons from 1-methyl-4-phenylpyridinium (MPP + ) insult, scavenge free radicals, and inhibit monoamine oxidase (MAO)/cholinesterase (ChE) activities. Among them, MT-20R exhibited the most potent MAO-B inhibition both in vitro and in vivo. We further investigated the neuroprotective effects of MT-20R using a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model. In vivo, MT-20R alleviated MPTP-induced motor deficits, raised the striatal contents of dopamine and its metabolites, and restored the expression of tyrosine hydroxylase (TH) and the number of TH-positive DA neurons in the substantia nigra. Additionally, MT-20R enhanced the expression of Bcl-2, decreased the expression of Bax and Caspase 3, and activated the AKT/Nrf2/HO-1 signaling pathway. These findings suggest that MT-20R may be a novel therapeutic candidate for treatment of PD.

  8. Aqueous extracts of avocado pear (Persea americana Mill.) leaves and seeds exhibit anti-cholinesterases and antioxidant activities in vitro.

    PubMed

    Oboh, Ganiyu; Odubanjo, Veronica O; Bello, Fatai; Ademosun, Ayokunle O; Oyeleye, Sunday I; Nwanna, Emem E; Ademiluyi, Adedayo O

    2016-03-01

    Avocado pear (Persea americana Mill.) leaves and seeds are used in traditional medicine for the treatment/management of Alzheimer disease (AD); however, information on the mechanism of actions is limited. This study sought to investigate the effect of P. americana leaf and seed aqueous extracts on some enzymes linked with AD (acetylcholinesterase [AChE] and butyrylcholinesterase [BChE] activities) and their antioxidant potentials in vitro. The inhibitory effects of extracts on AChE and BChE activities and antioxidant potentials (inhibition of Fe2+- and sodium nitroprusside-induced thiobarbiturate reactive species [TBARS] production in rat brain homogenates, radicals [1,1-diphenyl-2-picrylhydrazyl, hydroxyl, and nitric oxide] scavenging and iron [Fe] chelation abilities) were investigated. Phenolic content and phytochemical screening were carried out. Alkaloid profile was also determined using gas chromatography coupled with flame ionization detector (GC-FID). The extracts inhibited AChE and BChE activities and prooxidant-induced TBARS production in a dose-dependent manner, with the seed extract having the highest inhibitory effect and the leaf extract exhibiting higher phenolic content and radical scavenging abilities, but lower Fe chelation ability compared with that of the seed. The phytochemical screening revealed the presence of saponins, alkaloids, and terpenoids in both extracts, whereas the total alkaloid profile was higher in the seed extract than in the leaf extract, as revealed by GC-FID. The anti-cholinesterase and antioxidant activities of avocado leaf and seed could be linked to their phytoconstituents and might be the possible mechanisms underlying their use as a cheap and natural treatment/management of AD. However, these extracts should be further investigated in vivo.

  9. Efficacy of novel phenoxyalkyl pyridinium oximes as brain-penetrating reactivators of cholinesterase inhibited by surrogates of sarin and VX.

    PubMed

    Chambers, Janice E; Chambers, Howard W; Funck, Kristen E; Meek, Edward C; Pringle, Ronald B; Ross, Matthew K

    2016-11-25

    Pyridinium oximes are strong nucleophiles and many are effective reactivators of organophosphate-inhibited cholinesterase (ChE). However, the current oxime reactivators are ineffective at crossing the blood-brain barrier and reactivating brain ChE in the intact organism. Our laboratories have developed a series of substituted phenoxyalkyl pyridinium oximes (US patent 9,227,937 B2) with the goal of identifying reactivators effective in crossing the blood-brain barrier. The first 35 of the series were found to have similar in vitro efficacy as reactivators of ChE inhibited by a sarin surrogate (phthalimidyl isopropyl methylphosphonate, PIMP) or a VX surrogate (nitrophenyl ethyl methylphosphonate, NEMP) in bovine brain preparations as previously observed in rat brain preparations. A number of these novel oximes have shown the ability to decrease the level of ChE inhibition in the brains of rats treated with a high sublethal dosage of either a sarin surrogate (nitrophenyl isopropyl methylphosphonate, NIMP) or the VX surrogate NEMP. Levels of reactivation at 2 h after oxime administration were up to 35% while the currently approved therapeutic, 2-PAM, yielded no reduction in brain ChE inhibition. In addition, there was evidence of attenuation of seizure-like behavior with several of the more effective novel oximes, but not 2-PAM. Therefore these novel oximes have demonstrated an ability to reactivate inhibited ChE in brain preparations from two species and in vivo data support their ability to enter the brain and provide a therapeutic action. These novel oximes have the potential to be developed into improved antidotes for nerve agent therapy. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  10. Integrated Lateral Flow Test Strip with Electrochemical Sensor for Quantification of Phosphorylated Cholinesterase: Biomarker of Exposure to Organophosphorus Agents

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Du, Dan; Wang, Jun; Wang, Limin

    An integrated lateral flow test strip with electrochemical sensor (LFTSES) device with rapid, selective and sensitive response for quantification of exposure to organophosphorus (OP) pesticides and nerve agents has been developed. The principle of this approach is based on parallel measurements of post-exposure and baseline acetylcholinesterase (AChE) enzyme activity, where reactivation of the phosphorylated AChE is exploited to enable measurement of total amount of AChE (including inhibited and active) which is used as a baseline for calculation of AChE inhibition. Quantitative measurement of phosphorylated adduct (OP-AChE) was realized by subtracting the active AChE from the total amount of AChE. Themore » proposed LFTSES device integrates immunochromatographic test strip technology with electrochemical measurement using a disposable screen printed electrode which is located under the test zone. It shows linear response between AChE enzyme activity and enzyme concentration from 0.05 to 10 nM, with detection limit of 0.02 nM. Based on this reactivation approach, the LFTSES device has been successfully applied for in vitro red blood cells inhibition studies using chlorpyrifos oxon as a model OP agent. This approach not only eliminates the difficulty in screening of low-dose OP exposure because of individual variation of normal AChE values, but also avoids the problem in overlapping substrate specificity with cholinesterases and avoids potential interference from other electroactive species in biological samples. It is baseline free and thus provides a rapid, sensitive, selective and inexpensive tool for in-field and point-of-care assessment of exposures to OP pesticides and nerve agents.« less

  11. Effectiveness of switching to the rivastigmine transdermal patch from oral cholinesterase inhibitors: a naturalistic prospective study in Alzheimer's disease.

    PubMed

    Cagnin, Annachiara; Cester, Alberto; Costa, Bruno; Ermani, Mario; Gabelli, Carlo; Gambina, Giuseppe

    2015-03-01

    Oral donepezil and rivastigmine are two commonly used cholinesterase inhibitors (ChEIs) used in Alzheimer's disease (AD). The rivastigmine transdermal patch formulation has high tolerability profile, allowing patients to achieve optimal therapeutic doses and providing potential advantages over oral ChEIs. This is a 6-month, multicentre, observational efficacy and tolerability study of switching from oral ChEIs to rivastigmine patch in AD patients who failed to show benefit from previous treatment. The reasons of the switch were: (1) lack/loss of benefit from previous oral ChEI treatment; (2) tolerability problems. The primary outcome was cognitive changes measured with the mini-mental state examination (MMSE) test. Secondary outcomes were modifications of functional independence and behavioral disturbances and occurrence of adverse events (AEs) after switching. 174 patients, over 180 patients screened, entered the study (lack/loss of efficacy: 57 %, tolerability problems: 33 %, both reasons: 10 %). 6 months after switching 56 % of patients stabilized or increased the MMSE score respect to baseline. The only predictor of this outcome was the response at 3 months. In the group with lack/loss of response to oral ChEI, the decline of the MMSE score changed from -3.4 ± 2.5 points in the 6 months before switching to -0.5 ± 3.2 in the 6 months after the switch (p < 0.001). There were no significant changes in the IADL or NPI scores. Drug discontinuation rate was 20 %, due to AEs (18 %) and lack of compliance (2 %). Switching from an unsuccessful oral ChEI therapy to rivastigmine patch is effective and safe in more than half of the switched patients after a 6-month period.

  12. Acute Toxicity Estimation and Operational Risk Management of Chemical Warfare Agent Exposures

    DTIC Science & Technology

    2004-05-01

    Following absorption into the body, nerve agents bind with and inhibit the activity of cholinesterases (ChE) that are present in the blood and...other tissues. Blood ChE activity depression by itself is not considered an adverse effect but (particularly red blood cell cholinesterase (RBC-ChE...chemical, such as an organophosphate , that blocks nerve impulses by inhibiting the activity of the enzyme cholinesterase (adapted from University of

  13. Multitarget Therapeutic Leads for Alzheimer's Disease: Quinolizidinyl Derivatives of Bi- and Tricyclic Systems as Dual Inhibitors of Cholinesterases and β-Amyloid (Aβ) Aggregation.

    PubMed

    Tonelli, Michele; Catto, Marco; Tasso, Bruno; Novelli, Federica; Canu, Caterina; Iusco, Giovanna; Pisani, Leonardo; Stradis, Angelo De; Denora, Nunzio; Sparatore, Anna; Boido, Vito; Carotti, Angelo; Sparatore, Fabio

    2015-06-01

    Multitarget therapeutic leads for Alzheimer's disease were designed on the models of compounds capable of maintaining or restoring cell protein homeostasis and of inhibiting β-amyloid (Aβ) oligomerization. Thirty-seven thioxanthen-9-one, xanthen-9-one, naphto- and anthraquinone derivatives were tested for the direct inhibition of Aβ(1-40) aggregation and for the inhibition of electric eel acetylcholinesterase (eeAChE) and horse serum butyrylcholinesterase (hsBChE). These compounds are characterized by basic side chains, mainly quinolizidinylalkyl moieties, linked to various bi- and tri-cyclic (hetero)aromatic systems. With very few exceptions, these compounds displayed inhibitory activity on both AChE and BChE and on the spontaneous aggregation of β-amyloid. In most cases, IC50 values were in the low micromolar and sub-micromolar range, but some compounds even reached nanomolar potency. The time course of amyloid aggregation in the presence of the most active derivative (IC50 =0.84 μM) revealed that these compounds might act as destabilizers of mature fibrils rather than mere inhibitors of fibrillization. Many compounds inhibited one or both cholinesterases and Aβ aggregation with similar potency, a fundamental requisite for the possible development of therapeutics exhibiting a multitarget mechanism of action. The described compounds thus represent interesting leads for the development of multitarget AD therapeutics. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  14. 75 FR 17712 - Malathion and Diquat Dibromide; Cancellation Order for Amendments to Terminate Uses

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-04-07

    ... suggested that high levels of exposure to cholinesterase inhibitors such as OP insecticides - may cause a state of permanent hypersensitivity to cholinesterase inhibitors. Nonetheless, the commenter supported...

  15. 21 CFR 520.2520e - Trichlorfon boluses.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... § 510.600(c) of this chapter. (c) Special considerations. Trichlorfon is a cholinesterase inhibitor. Do... or exposure to, neuromuscular depolarizing agents (i.e., succinylcholine) or to cholinesterase...

  16. 21 CFR 520.2520e - Trichlorfon boluses.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... § 510.600(c) of this chapter. (c) Special considerations. Trichlorfon is a cholinesterase inhibitor. Do... or exposure to, neuromuscular depolarizing agents (i.e., succinylcholine) or to cholinesterase...

  17. 21 CFR 520.2520e - Trichlorfon boluses.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... § 510.600(c) of this chapter. (c) Special considerations. Trichlorfon is a cholinesterase inhibitor. Do... or exposure to, neuromuscular depolarizing agents (i.e., succinylcholine) or to cholinesterase...

  18. 21 CFR 520.2520e - Trichlorfon boluses.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... § 510.600(c) of this chapter. (c) Special considerations. Trichlorfon is a cholinesterase inhibitor. Do... or exposure to, neuromuscular depolarizing agents (i.e., succinylcholine) or to cholinesterase...

  19. Effects of sublethal fenitrothion ingestion on cholinesterase inhibition, standard metabolism, thermal preference, and prey-capture ability in the Australian central bearded dragon (Pogona vitticeps, Agamidae).

    PubMed

    Bain, David; Buttemer, William A; Astheimer, Lee; Fildes, Karen; Hooper, Michael J

    2004-01-01

    The central bearded dragon (Pogona vitticeps) is a medium-sized lizard that is common in semiarid habitats in Australia and that potentially is at risk of fenitrothion exposure from use of the chemical in plague locust control. We examined the effects of single sublethal doses of this organophosphate (OP; low dose = 2.0 mg/kg; high dose = 20 mg/kg; control = vehicle alone) on lizard thermal preference, standard metabolic rate, and prey-capture ability. We also measured activities of plasma total cholinesterase (ChE) and acetylcholinesterase before and at 0, 2, 8, 24, 120, and 504 h after OP dosing. Predose plasma total ChE activity differed significantly between sexes and averaged 0.66 +/- 0.06 and 0.45 +/- 0.06 micromol/min/ml for males and females, respectively. Approximately 75% of total ChE activity was attributable to butyrylcholinesterase. Peak ChE inhibition reached 19% 2 h after OP ingestion in the low-dose group, and 68% 8 h after ingestion in high-dose animals. Neither OP doses significantly affected diurnal body temperature, standard metabolic rate, or feeding rate. Plasma total ChE levels remained substantially depressed up to 21 d after dosing in the high-dose group, making this species a useful long-term biomonitor of OP exposure in its habitat.

  20. Measurement of cholinesterase enzyme activity before and after exposure to organophosphate pesticides in farmers of a suburb region of Mazandaran, a northern province of Iran.

    PubMed

    Pakravan, N; Shokrzadeh, M; Bari, M A Khalat; Shadboorestan, Amir

    2016-03-01

    Accidental toxicity by organophosphate (OP) agents may occur among farmers during spraying season due to improper use and handling. Plasma cholinesterase (ChE) activity measurement is recommended to monitor the extent of exposure to the OP agent. The aim of the current study was to measure plasma ChE activity before and after exposure with OP pesticides. This was a prospective study conducted on 36 farmers working in the farm field. The plasma ChE level was measured before spraying and 2 days and 8 weeks after spraying season and exposure to OP agent. Farmers were observed for clinical signs and symptoms of toxicity after exposure. Vertimac was the most common agent used by farmers followed by diazinon and chlorpyrifos. The plasma ChE level significantly decreased after exposure by over 50%. The level returned to preexposure level after 8 weeks. Exposure to OP pesticide is a major concern in the developing countries. More than 50% reduction in the plasma ChE activity after spraying is an alarming message for health-care system and policy makers. Furthermore, workplace evaluation, serial ChE monitoring, and appropriate training and education to exposed individuals would be initial important steps to avoid the toxicity or reduce the severity of poisoning. © The Author(s) 2015.