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Murray E. Selkirk - One of the best experts on this subject based on the ideXlab platform.
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Natural genomic amplification of Cholinesterase genes in animals.
Journal of neurochemistry, 2017Co-Authors: Arnaud Chatonnet, Nicolas Lenfant, Pascale Marchot, Murray E. SelkirkAbstract: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.
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Natural genomic amplification of Cholinesterase genes in animals
Journal of Neurochemistry, 2017Co-Authors: Arnaud Chatonnet, Nicolas Lenfant, Pascale Marchot, Murray E. SelkirkAbstract: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, zebra fish 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.
Arnaud Chatonnet - One of the best experts on this subject based on the ideXlab platform.
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Comparative mapping of selected structural determinants on the extracellular domains of Cholinesterase-like cell-adhesion molecules.
Neuropharmacology, 2020Co-Authors: Davide Comoletti, Arnaud Chatonnet, Yves Bourne, Laura Trobiani, Pascale MarchotAbstract:Cell adhesion generally involve formation of homophilic or heterophilic protein complexes between two cells to form transcellular junctions. Neural cell-adhesion members of the α/β-hydrolase fold superfamily of proteins use their extracellular or soluble Cholinesterase-like domain to bind cognate partners across cell membranes, as illustrated by the neuroligins. These cell-adhesion molecules currently comprise the synaptic organizers neuroligins found in all phyla, along with three proteins found only in invertebrates: the guidance molecule neurotactin, the glia-specific gliotactin, and the basement membrane protein glutactin. Although these proteins share a Cholinesterase-like fold, they lack one or more residues composing the catalytic triad responsible for the enzymatic activity of the Cholinesterases. Conversely, they are found in various subcellular localisations and display specific disulfide bonding and N-glycosylation patterns, along with individual surface determinants possibly associated with recognition and binding of protein partners. Formation of non-covalent dimers typical of the Cholinesterases is documented for mammalian neuroligins, yet whether invertebrate neuroligins and their neurotactin, gliotactin and glutactin relatives also form dimers in physiological conditions is unknown. Here we provide a brief overview of the localization, function, evolution, and conserved versus individual structural determinants of these Cholinesterase-like cell-adhesion proteins.
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An evolutionary perspective on the first disulfide bond in members of the Cholinesterase-carboxylesterase (COesterase) family: Possible outcomes for Cholinesterase expression in prokaryotes
Chemico-Biological Interactions, 2019Co-Authors: Arnaud Chatonnet, Nicolas Lenfant, Pascale Marchot, Thierry Hotelier, Xavier Brazzolotto, Yves BourneAbstract:Within the alpha/beta hydrolase fold superfamily of proteins, the COesterase group (carboxylesterase type B, block C, Cholinesterases …) diverged from the other groups through simultaneous integration of an N-terminal, first disulfide bond and a significant increase in the protein mean size. This first disulfide bond ties a large Cys loop, which in the Cholinesterases is named the omega loop and forms the upper part of the active center gorge, essential for the high catalytic activity of these enzymes. In some non-catalytic members of the family, the loop may be necessary for heterologous partner recognition. Reshuffling of this protein portion occurred at the time of emergence of the fungi/metazoan lineage. Homologous proteins with this first disulfide bond are absent in plants but they are found in a limited number of bacterial genomes. In prokaryotes, the genes coding for such homologous proteins may have been acquired by horizontal transfer. However, the cysteines of the first disulfide bond are often lost in bacteria. Natural expression in bacteria of CO-esterases comprising this disulfide bond may have required compensatory mutations or expression of new chaperones. This disulfide bond may also challenge expression of the eukaryote-specific Cholinesterases in prokaryotic cells. Yet recently, catalytically active human Cholinesterase variants with enhanced thermostability were successfully expressed in E. coli. The key was the use of a peptidic sequence optimized through the Protein Repair One Stop Shop process, an automated structure- and sequence-based algorithm for expression of properly folded, soluble and stable eukaryotic proteins. Surprisingly however, crystal structures of the optimized Cholinesterase variants expressed in bacteria revealed co-existing formed and unformed states of the first disulfide bond. Whether the bond never formed, or whether it properly formed then broke during the production/analysis process, cannot be inferred from the structural data. Yet, these features suggest that the recently acquired first disulfide bond is difficult to maintain in E. coli-expressed Cholinesterases. To explore the fate of the first disulfide bond throughout the Cholinesterase relatives, we reanalyzed the crystal structures of representative COesterases members from natural prokaryotic or eukaryotic sources or produced as recombinant proteins in E. coli. We found that in most cases this bond is absent.
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Natural genomic amplification of Cholinesterase genes in animals.
Journal of neurochemistry, 2017Co-Authors: Arnaud Chatonnet, Nicolas Lenfant, Pascale Marchot, Murray E. SelkirkAbstract: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.
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Natural genomic amplification of Cholinesterase genes in animals
Journal of Neurochemistry, 2017Co-Authors: Arnaud Chatonnet, Nicolas Lenfant, Pascale Marchot, Murray E. SelkirkAbstract: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, zebra fish 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.
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Tracking origin and divergence of Cholinesterases and Neuroligins
2013Co-Authors: Nicolas Lenfant, Pascale Marchot, Thierry Hotelier, Yves Bourne, Arnaud ChatonnetAbstract:Cholinesterase activity can be found in all kingdoms of living organism, yet Cholinesterases involved in cholinergic transmission appeared only recently in the animal phylum [1]. The closest proteins homologous to the Cholinesterases are the neuroligins. These proteins with an altered catalytic triad and no identified hydrolytic activity have well-identified cell adhesion properties. Comparing evolution of the Cholinesterases and neuroligins with other proteins involved in synapse functioning may shed light on the common or divergent developmental regulation events involved into the setting and maintenance of cholinergic transmission versus the balance between inhibitory and excitatory synapses. This comparison and its implications will be presented.
Pascale Marchot - One of the best experts on this subject based on the ideXlab platform.
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Comparative mapping of selected structural determinants on the extracellular domains of Cholinesterase-like cell-adhesion molecules.
Neuropharmacology, 2020Co-Authors: Davide Comoletti, Arnaud Chatonnet, Yves Bourne, Laura Trobiani, Pascale MarchotAbstract:Cell adhesion generally involve formation of homophilic or heterophilic protein complexes between two cells to form transcellular junctions. Neural cell-adhesion members of the α/β-hydrolase fold superfamily of proteins use their extracellular or soluble Cholinesterase-like domain to bind cognate partners across cell membranes, as illustrated by the neuroligins. These cell-adhesion molecules currently comprise the synaptic organizers neuroligins found in all phyla, along with three proteins found only in invertebrates: the guidance molecule neurotactin, the glia-specific gliotactin, and the basement membrane protein glutactin. Although these proteins share a Cholinesterase-like fold, they lack one or more residues composing the catalytic triad responsible for the enzymatic activity of the Cholinesterases. Conversely, they are found in various subcellular localisations and display specific disulfide bonding and N-glycosylation patterns, along with individual surface determinants possibly associated with recognition and binding of protein partners. Formation of non-covalent dimers typical of the Cholinesterases is documented for mammalian neuroligins, yet whether invertebrate neuroligins and their neurotactin, gliotactin and glutactin relatives also form dimers in physiological conditions is unknown. Here we provide a brief overview of the localization, function, evolution, and conserved versus individual structural determinants of these Cholinesterase-like cell-adhesion proteins.
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An evolutionary perspective on the first disulfide bond in members of the Cholinesterase-carboxylesterase (COesterase) family: Possible outcomes for Cholinesterase expression in prokaryotes
Chemico-Biological Interactions, 2019Co-Authors: Arnaud Chatonnet, Nicolas Lenfant, Pascale Marchot, Thierry Hotelier, Xavier Brazzolotto, Yves BourneAbstract:Within the alpha/beta hydrolase fold superfamily of proteins, the COesterase group (carboxylesterase type B, block C, Cholinesterases …) diverged from the other groups through simultaneous integration of an N-terminal, first disulfide bond and a significant increase in the protein mean size. This first disulfide bond ties a large Cys loop, which in the Cholinesterases is named the omega loop and forms the upper part of the active center gorge, essential for the high catalytic activity of these enzymes. In some non-catalytic members of the family, the loop may be necessary for heterologous partner recognition. Reshuffling of this protein portion occurred at the time of emergence of the fungi/metazoan lineage. Homologous proteins with this first disulfide bond are absent in plants but they are found in a limited number of bacterial genomes. In prokaryotes, the genes coding for such homologous proteins may have been acquired by horizontal transfer. However, the cysteines of the first disulfide bond are often lost in bacteria. Natural expression in bacteria of CO-esterases comprising this disulfide bond may have required compensatory mutations or expression of new chaperones. This disulfide bond may also challenge expression of the eukaryote-specific Cholinesterases in prokaryotic cells. Yet recently, catalytically active human Cholinesterase variants with enhanced thermostability were successfully expressed in E. coli. The key was the use of a peptidic sequence optimized through the Protein Repair One Stop Shop process, an automated structure- and sequence-based algorithm for expression of properly folded, soluble and stable eukaryotic proteins. Surprisingly however, crystal structures of the optimized Cholinesterase variants expressed in bacteria revealed co-existing formed and unformed states of the first disulfide bond. Whether the bond never formed, or whether it properly formed then broke during the production/analysis process, cannot be inferred from the structural data. Yet, these features suggest that the recently acquired first disulfide bond is difficult to maintain in E. coli-expressed Cholinesterases. To explore the fate of the first disulfide bond throughout the Cholinesterase relatives, we reanalyzed the crystal structures of representative COesterases members from natural prokaryotic or eukaryotic sources or produced as recombinant proteins in E. coli. We found that in most cases this bond is absent.
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Natural genomic amplification of Cholinesterase genes in animals.
Journal of neurochemistry, 2017Co-Authors: Arnaud Chatonnet, Nicolas Lenfant, Pascale Marchot, Murray E. SelkirkAbstract: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.
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Natural genomic amplification of Cholinesterase genes in animals
Journal of Neurochemistry, 2017Co-Authors: Arnaud Chatonnet, Nicolas Lenfant, Pascale Marchot, Murray E. SelkirkAbstract: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, zebra fish 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.
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Tracking origin and divergence of Cholinesterases and Neuroligins
2013Co-Authors: Nicolas Lenfant, Pascale Marchot, Thierry Hotelier, Yves Bourne, Arnaud ChatonnetAbstract:Cholinesterase activity can be found in all kingdoms of living organism, yet Cholinesterases involved in cholinergic transmission appeared only recently in the animal phylum [1]. The closest proteins homologous to the Cholinesterases are the neuroligins. These proteins with an altered catalytic triad and no identified hydrolytic activity have well-identified cell adhesion properties. Comparing evolution of the Cholinesterases and neuroligins with other proteins involved in synapse functioning may shed light on the common or divergent developmental regulation events involved into the setting and maintenance of cholinergic transmission versus the balance between inhibitory and excitatory synapses. This comparison and its implications will be presented.
Nicolas Lenfant - One of the best experts on this subject based on the ideXlab platform.
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An evolutionary perspective on the first disulfide bond in members of the Cholinesterase-carboxylesterase (COesterase) family: Possible outcomes for Cholinesterase expression in prokaryotes
Chemico-Biological Interactions, 2019Co-Authors: Arnaud Chatonnet, Nicolas Lenfant, Pascale Marchot, Thierry Hotelier, Xavier Brazzolotto, Yves BourneAbstract:Within the alpha/beta hydrolase fold superfamily of proteins, the COesterase group (carboxylesterase type B, block C, Cholinesterases …) diverged from the other groups through simultaneous integration of an N-terminal, first disulfide bond and a significant increase in the protein mean size. This first disulfide bond ties a large Cys loop, which in the Cholinesterases is named the omega loop and forms the upper part of the active center gorge, essential for the high catalytic activity of these enzymes. In some non-catalytic members of the family, the loop may be necessary for heterologous partner recognition. Reshuffling of this protein portion occurred at the time of emergence of the fungi/metazoan lineage. Homologous proteins with this first disulfide bond are absent in plants but they are found in a limited number of bacterial genomes. In prokaryotes, the genes coding for such homologous proteins may have been acquired by horizontal transfer. However, the cysteines of the first disulfide bond are often lost in bacteria. Natural expression in bacteria of CO-esterases comprising this disulfide bond may have required compensatory mutations or expression of new chaperones. This disulfide bond may also challenge expression of the eukaryote-specific Cholinesterases in prokaryotic cells. Yet recently, catalytically active human Cholinesterase variants with enhanced thermostability were successfully expressed in E. coli. The key was the use of a peptidic sequence optimized through the Protein Repair One Stop Shop process, an automated structure- and sequence-based algorithm for expression of properly folded, soluble and stable eukaryotic proteins. Surprisingly however, crystal structures of the optimized Cholinesterase variants expressed in bacteria revealed co-existing formed and unformed states of the first disulfide bond. Whether the bond never formed, or whether it properly formed then broke during the production/analysis process, cannot be inferred from the structural data. Yet, these features suggest that the recently acquired first disulfide bond is difficult to maintain in E. coli-expressed Cholinesterases. To explore the fate of the first disulfide bond throughout the Cholinesterase relatives, we reanalyzed the crystal structures of representative COesterases members from natural prokaryotic or eukaryotic sources or produced as recombinant proteins in E. coli. We found that in most cases this bond is absent.
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Natural genomic amplification of Cholinesterase genes in animals.
Journal of neurochemistry, 2017Co-Authors: Arnaud Chatonnet, Nicolas Lenfant, Pascale Marchot, Murray E. SelkirkAbstract: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.
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Natural genomic amplification of Cholinesterase genes in animals
Journal of Neurochemistry, 2017Co-Authors: Arnaud Chatonnet, Nicolas Lenfant, Pascale Marchot, Murray E. SelkirkAbstract: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, zebra fish 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.
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Tracking origin and divergence of Cholinesterases and Neuroligins
2013Co-Authors: Nicolas Lenfant, Pascale Marchot, Thierry Hotelier, Yves Bourne, Arnaud ChatonnetAbstract:Cholinesterase activity can be found in all kingdoms of living organism, yet Cholinesterases involved in cholinergic transmission appeared only recently in the animal phylum [1]. The closest proteins homologous to the Cholinesterases are the neuroligins. These proteins with an altered catalytic triad and no identified hydrolytic activity have well-identified cell adhesion properties. Comparing evolution of the Cholinesterases and neuroligins with other proteins involved in synapse functioning may shed light on the common or divergent developmental regulation events involved into the setting and maintenance of cholinergic transmission versus the balance between inhibitory and excitatory synapses. This comparison and its implications will be presented.
Kamil Kuca - One of the best experts on this subject based on the ideXlab platform.
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The progress in the Cholinesterase quantification methods.
Expert opinion on drug discovery, 2012Co-Authors: Ondrej Holas, Miroslav Pohanka, Kamil Musilek, Kamil KucaAbstract:Introduction: 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. Areas covered: 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, ...
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Potency of novel oximes to reactivate sarin inhibited human Cholinesterases.
Drug and chemical toxicology, 2008Co-Authors: Daniel Jun, Kamil Kuca, Jan Pícha, Vit Koleckar, Jan MarekAbstract:Class of monoquaternary pyridinium oximes was in vitro tested as potential reactivators of acetylCholinesterase (AChE; EC 3.1.1.7) inhibited by nerve agent sarin. Human brain homogenate was used as an appropriate source of Cholinesterases. Reactivation potency of novel oximes was compared with currently available reactivators—pralidoxime, obidoxime, and HI-6. According to the obtained results, only five reactivators were able to satisfactorily renew Cholinesterase potency (pralidoxime, obidoxime, HI-6, 4-PAM, and K119). Unfortunately, none of the novel tested reactivators surpassed the reactivation potency of the currently most promising reactivator, HI-6. This study shows that monoquaternary reactivators are unable to reactivate nerve agent–inhibited AChE. Due to this, in future, only bisquaternary compounds derived from HI-6 or obidoxime should be designed as new potential Cholinesterase reactivators.
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evaluation of reactivation test in anaesthetized dogs with experimental intoxication with nerve agents
Journal of Applied Toxicology, 2006Co-Authors: Jiri Bajgar, Lucie Bartosova, Josef Fusek, Kamil KucaAbstract:Following repeated antidotal treatment of anaesthetized dogs (1 min with atropine, 10 min with atropine and obidoxime, 60 min with atropine and obidoxime) after the intoxication with soman, sarin and VX (1 × LD50, i.m.), the blood Cholinesterases (erythrocyte, whole blood, plasma) were monitored and their reactivatability (whole blood) was determined. During this treatment, the activities of erythrocyte acetylCholinesterase (AChE), plasma butyrylCholinesterase (BuChE) and whole blood Cholinesterases were monitored. Atropine and obidoxime did not affect Cholinesterase activities in control animals, whereas administration of obidoxime to dogs intoxicated with nerve agent caused an increase in the Cholinesterase activities. The sensitivity of Cholinesterases decreased in the order erythrocyte AChE > whole blood Cholinesterases > plasma BuChE, respectively. Following sarin intoxication, blood Cholinesterases were increased after the obidoxime administration. Intoxication with VX showed a similar picture but reactivation after the obidoxime administration was greater. In soman intoxication, the picture of Cholinesterase changes was similar during the first 30 min of treatment. Then the increase in AChE activity following obidoxime administration was not as high as in the case of sarin and VX intoxication. Thus, the reactivation efficacy of obidoxime during nerve agent intoxication indicates that its repeated administration could be easily monitored using the reactivation test. Copyright © 2006 John Wiley & Sons, Ltd.