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

Botulinum toxin type A (BTx), which blocks quantal and partially reduces spontaneous nonquantal acetylcholine (ACh) release at neuromuscular junctions, was tested for its possible attenuating effect on diisopropylphosphorofluoridate (DFP)-induced muscle lesions. The extent of muscle lesion in extensor digitorum longus and soleus muscle of DFP injected rats with and without BTx pretreatment was evaluated using light and electron microscopic procedures. In parallel experiments, acetylcholinesterase (AChE) activity was measured and the functional state of muscles in experimental groups was determined by electrophysiological methods. The results show that pretreatment with BTx almost completely protects the muscles from DFP-induced spontaneous activity and lesions in spite of critically inhibited synaptic AChE. These results are consistent with the conclusion that the effect is not mediated by direct action of organophosphate on muscle, but by the accumulation of ACh resulting in muscle hyperactivity. Therefore, it is concluded that in conditions of acutely inhibited synaptic AChE, the quantal release of ACh is essential for lesion induction, whereas the spontaneous nonquantal ACh release, which is only partially affected in BTx-blocked nerve endings, seems not to be involved.
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PMID:Prevention of diisopropylphosphorofluoridate-induced myopathy by botulinum toxin type A blockage of quantal release of acetylcholine. 192 69

Anticholinesterases (anti-ChE) have some effects on biological properties including behavior, vision, and electroencephalograms, which are often long lasting and which do not appear to be due to cholinesterase (ChE; EC 3.1.1.7) inhibition, but which may be due to alterations in the organization and/or functioning of the cellular membrane. We assessed the effects of anti-ChE agents on the asymmetric organization of proteins in the innervated (excitable) and in the non-innervated (non-excitable) plasma membrane of the electroplax from the electric eel. Lactoperoxidase-catalyzed iodination (LCI) was carried out under impenetrable conditions in intact electroplax (where protein exposure on the external surface is monitored) and in split electroplax (where total protein labeling on both the external and internal monolayers of the plasma membrane bilayer is monitored). Labeling in split electroplax was much greater than in intact electroplax for all molecular weight groupings of proteins (30,000 to greater than 200,000). The anti-ChE agents diisopropyl phosphofluoridate (DFP; 10(-3) M), sarin (10(-4) M) and soman (10(-4) M, 10(-6) M, 2.5 x 10(-9) M) did not alter permeability, protein content or the electrophoretic pattern of the plasma membrane proteins of the electroplax. DFP, sarin and 10(-6) M soman (but not 2.5 x 10(-9) M or 10(-4) M soman) increased labeling of some of the molecular weight fractions in the non-innervated plasma membrane as monitored by LCI in intact electroplax. Under these same conditions, DFP and 10(-4) M soman increased labeling in the innervated plasma membrane while 10(-6) M soman decreased labeling. When LCI was carried out in split electroplax, 10(-4) M soman caused a decrease in labeling in both the innervated and non-innervated plasma membrane indicating a decrease of exposed proteins on the cytoplasmic surface of the plasma membrane. These concentrations of the anti-ChE agents caused almost complete ChE inhibition in the electroplax cells, except for 2.5 x 10(-9) M soman which caused little or no inhibition. These results suggest that alterations in protein asymmetry, as monitored by LCI of accessible proteins, are not directly due to ChE inhibition. These changes in organization of membrane proteins could contribute to a variety of effects of anti-ChE agents which are not due to ChE inhibition.
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PMID:Effects of diisopropyl phosphofluoridate, sarin and soman on the accessibility of proteins, in the electroplax membrane, to lactoperoxidase-catalyzed iodination. 193 Feb 70

Different drug combinations consisting of cholinolytic and a cholinesterase (ChE) reactivator provide greater therapeutic efficacy in acute organophosphorus (OP) poisoning in mice than when used alone. Maximum protection, as determined by a shift of the LD50 for the two OP agents, was observed with the cholinolytic benactyzine. A protection index (P.I.) of 42 was obtained when benactyzine was given along with obidoxime in diisopropylphosphorofluoridate (DFP) intoxication. With the more toxic OP agent soman (o-pinacolylmethylphosphonofluoridate), the same cholinolytic only offered a maximum P.I. of 3.2 when administered with HS-6, another bispyridinium ChE reactivator. This beneficial effect of benactyzine is possibly due to its greater antimuscarinic effect in the central nervous system than atropine or dexetimide.
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PMID:Actions and interactions of cholinolytics and cholinesterase reactivators in the treatment of acute organophosphorus toxicity. 193 7

This study examined the effects of the organophosphorus delayed neurotoxicant bis (1-methylethyl) phosphorofluoridate (DFP) on the central nervous system of the European ferret. Animals received subcutaneous injections of either 2 or 4 mg DFP/kg b.w. The extent of neuropathology was determined by the Fink-Heimer method, the activities of neuropathy target esterase (NTE) and cholinesterase (ChE) by enzyme assay methods, and the severity of clinical signs by a graded scale. In ferrets injected with 4 mg DFP/kg b.w., dense axonal and terminal degeneration were noted at 21 and 28 days post-DFP in the gracile, inferior vestibular, and lateral reticular nuclei, medial and dorsal accessory nuclei of the inferior olive, and in cerebellar folia I-IV. Degeneration was also noted in laminae VI-VII throughout most of the spinal cord and in the ventral motor nucleus at the level of the cervical enlargement. Both NTE and ChE activities were maximally inhibited at 6 hr post-dosing. NTE activity returned to control levels by 4 days while ChE activities reached control levels at 21 days. Clinical signs at 21 and 28 days post-DFP ranged from slight hindlimb weakness to severe ataxia or hindlimb paralysis. Less severe degeneration and clinical signs were noted in the animals exposed to 2 mg DFP/kg b.w. These findings indicate that the European ferret may be a model species for assessing the effects of organophosphorus delayed neurotoxicants.
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PMID:Delayed neurotoxic effects of bis (1-methylethyl) phosphorofluoridate (DFP) in the European ferret: a possible mammalian model for organophosphorus-induced delayed neurotoxicity. 195 82

Ganglionic effects of the histamine H2 receptor antagonists cimetidine, ranitidine and 1-nitro-2-(2-propynylamino)-2-(2-[dimethylaminomethyl-2-furanyl) methylthiol]-ethylamino)ethylene (ORF 17578) were compared in the isolated superior cervical ganglion of the rat. Extracellular recording of compound action potentials showed that the drugs caused concentration-dependent inhibition of ganglionic transmission, as indicated by depression of the postganglionic compound action potential. Cimetidine-induced inhibition of ganglionic transmission was stimulus frequency-dependent. Increasing the Ca2+ from 2.2 to 4.4 mM in the bathing solution did not significantly affect the inhibitory actions of these agents. In the series with ranitidine, pretreatment with DFP to inhibit acetylcholinesterase similarly had no significant effect on the depression of the compound action potential by ranitidine. All three agents had little or no effect on nerve conduction in isolated vagi of the rat. The results indicate that all three histamine H2 receptor blockers inhibited ganglionic transmission, but only in large concentrations. The results also suggest that the blocking effect of these drugs was unrelated to their reported anticholinesterase action or to blockade of histamine H2 receptors, which are believed to exist on the presynaptic membrane. It is suggested that the ganglion effect may be due to the action of these agents on the acetylcholine receptor-ion channel complex in the postsynaptic membrane.
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PMID:A comparative study of the actions of histamine H2 receptor antagonists on transmission in the isolated superior cervical ganglion of the rat. 197 Jan 32

(1) Microsomal membranes from white rabbit muscle enriched in sarcoplasmic reticulum (SR) were used to investigate the preferential localization of acetylcholinesterase (AChE) in these membranes. (2) Integrity and orientation of the vesicles was assessed by measuring the inulin-inaccessible space of the vesicles and its calcium-loading capacity. (3) Treatment of the membranes with diisopropyl phosphorofluoridate (DFP), an irreversible inhibitor which is free soluble in lipid, produced an almost complete inactivation of AChE. The inhibition was prevented in assays performed with the non-permeant reversible inhibitor BW 284c51 (BW). (4) Similar results were obtained if echothiophate iodide (ECHO), an irreversible and poorly permeant inhibitor, instead of DFP was used. (5) Sedimentation profiles of enzyme solubilized with Triton X-100 from membranes inhibited by DFP after protection with BW showed a minor reduction in the relative proportion of a 4.5 S (G1) form. (6) Treatment of intact or saponin-permeabilized membranes with concanavalin A (ConA) produced enzyme-lectin complexes. In both cases, most of the enzyme was recovered in the sedimented complexes after centrifugation of the Triton-solubilized membranes. (7) Incubation of intact membranes with the antibody AE1 led to the formation of immuno complexes. Sedimentation analyses of the molecular forms of AChE revealed a shift in the sedimentation coefficients, whether the antibody was added before or after solubilization of the enzyme. (8) These results firmly establish an external localization of AChE in SR, most of the protein backbone facing the cytoplasmic side of the membrane.
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PMID:Acetylcholinesterase is orientated facing the cytoplasmic side in membranes derived from sarcoplasmic reticulum. 199 25

Diisopropyl phosphorofluoridate (DFP), an insecticide, is a potent anticholinesterase that binds essentially irreversibly to acetylcholinesterase, resulting in severe, acute neurologic pathology, and less severe, but longer-lasting, delayed neuropathy. We report here on the short-term effects of bath-applied DFP on extracellularly recorded responses from CA3 and CA1 of rat hippocampus. Exposure to 10 microM DFP evokes low amplitude, spontaneous bursts in CA3 generally within 10 minutes, and the bursting does not reverse with washing. The CA1 neuronal population usually bursts synchronously with CA3, but the population events are of low amplitude and sometimes not detectable, implying a differential sensitivity to DFP. These effects were partially blocked by the muscarinic antagonist atropine, while the cholinergic antagonist gallamine had little effect. Also, the reversible anticholinesterase physostigmine could, within temporal limits, protect slices from DFP's effects, implicating the cholinergic system as the probable mediator in the first stages of DFP-induced epileptogenesis.
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PMID:Effects of diisopropyl phosphorofluoridate (DFP) on CA3 and CA1 responses in rat hippocampus. 209 78

The recovery rate of brain cholinesterase activity (ChE) and muscarinic acetylcholine receptor sites (MAChRs) following a reduction due to a repeated treatment (2 weeks) with the antiChE agent, isofluorophate (diisopropyl fluorophosphate, DFP) was studied in young (3 months) and aged (24 months) male Sprague-Dawley rats. At the end of DFP treatment the inhibition of ChE in the cerebral cortex, hippocampus and striatum did not differ between young and aged rats (about 70%); the down-regulation of MAChRs (without changes in affinity) varied from 20 to 40% for various areas of brains of rats belonging to the two age-groups, and was the most pronounced in the cerebral cortex of aged rats. As assessed by factorial analysis of variance (2 ages x 2 recoveries ANOVA) there were age-related differences in the recovery rate of both ChE and MAChRs during 5 weeks from the end of DFP treatment. The impairment of recovery observed in aged rats was present in three brain areas and was the most pronounced in the cerebral cortex. Choline acetyltransferase (ChAT) was not influenced by the age and/or treatment in the cerebral cortex and hippocampus while in the striatum an age-related decline was observed. The overall data appear of interest in relation to the recent use of antiChE organophosphorus compounds in the therapy of age-related memory disorders.
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PMID:Age-related differences in the recovery rate of brain cholinesterases, choline acetyltransferase and muscarinic acetylcholine receptor sites after a subacute intoxication of rats with the anticholinesterase agent, isofluorophate. 213 Jun 46

In a recent study (9) it was found in rats that chronic treatment with the irreversible cholinesterase inhibitors DFP or soman led to behavioral tolerance in the case of DFP, but not in the case of soman. Biochemically, no explanation was found for this difference between these two inhibitors. Notably, chronic administration of each of these inhibitors did not affect the availability of the nicotinic receptors at the motor endplate, in spite of very low cholinesterase activity. In an attempt to explain the different effects of these inhibitors a neurophysiological approach seemed appropriate. The spontaneous quantal release of acetylcholine from diaphragm muscles in vitro from animals chronically treated with each inhibitor showed a similar trend; compared with controls the MEPP frequency was decreased, which was significant for DFP, and the MEPP amplitude was increased, which was significant for soman. Neuromuscular function of muscle strips obtained from both DFP- or soman-treated animals appeared significantly more sensitive to additional inhibitor added in vitro. This could simply be explained by the high preexisting level of cholinesterase inhibition, but seems in contrast with the phenomenon of tolerance.
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PMID:On the development of behavioral tolerance to organophosphates. II: Neurophysiological aspects. 215 28

Reports that near-lethal doses of the pesticide methamidophos (O,S-dimethyl phosphoramidothioate) caused a delayed neurotoxicity (OPIDN) in humans and that another phosphoramidate, isofenphos, caused OPIDN in the hen at high doses, prompted a study of the abilities of acephate (O,S-dimethyl acetylphosphoramidothioate) to inhibit brain acetylcholinesterase (AChE) and neuropathy target esterase (NTE) in vivo. Hens were treated orally with 5-700 mg/kg of acephate, or im with 50-200 micrograms/kg of diisopropyl-fluorophosphate (DFP, positive control) and sacrificed 24 hr later. Brain homogenates were assayed for AChE as an estimate of acute toxicity, for NTE to indicate acephate's potential to cause OPIDN, and for residues of acephate and its metabolite methamidophos. A range finding study confirmed the LD50 level for acephate was approximately 800 mg/kg. Regression analyses indicated an ID50 (a dose that inhibits 50% of activity) for acephate inhibition of AChE of 10 mg/kg and an extrapolated ID50 for inhibition of NTE of 1300 mg/kg, almost twice the LD50. In contrast, ID50 values for DFP were similar for AChE (146 micrograms/kg) and NTE (132 micrograms/kg). Brain methamidophos levels were 10 to 16 percent of the total acephate plus methamidophos brain concentration. The lower the dose of acephate, the higher was the relative percentage of methamidophos. The results show acephate is a more potent inhibitor of AChE than it is of NTE in hens and suggest it would be difficult to administer a single dose of acephate sufficient to cause OPIDN without killing the animal.
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PMID:Acetylcholinesterase and neuropathy target esterase in chickens treated with acephate. 228 53


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