Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.1.8 (cholinesterase)
 12,691 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several earlier studies showed that, in contrast with DFP, repeated injections with soman did not lead to behavioral tolerance in rats. The reason for the difference between the effects of these two organophosphate cholinesterase inhibitors was not clear and a neurophysiological approach was undertaken. Four experiments (A, B, C and D) were carried out, each consisting of three groups of rats, SC injected with saline, DFP (600 micrograms/kg) or soman (60 micrograms/kg) respectively. In Experiment B and D the rats were trained to criterion in a two-way shuttlebox. Thereafter, the animals of Experiment B were fitted with suitable electrodes and two days later their EEGs and visual evoked responses (VERs) were recorded, 1 and 24 h after a single dose of the above-mentioned compounds. In Experiment D the trained animals were subsequently injected 3 times per week for 4 weeks with the same doses and their performance was tested 5 days per week, 1 and 24 h after injection. After those 4 weeks, when the DFP-treated animals had developed behavioral tolerance, electrodes were fitted and EEGs and VERs were recorded after two days, again 1 and 24 h after injection, as in Experiment B. The difference with Experiments A and C was that these animals were not trained. Otherwise, treatment schedules and recording procedures of Experiment A were identical to those of Experiments B and of Experiment C to those of Experiment D. In all cases the EEGs and VERs were recorded from animals slowly walking in a rotating hollow transparent wheel. The results show a similar pattern in all four experiments.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:On the development of behavioral tolerance to organophosphates. IV: EEGand visual evoked responses. 176 3

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

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

As part of a study on the mechanisms underlying behavioral tolerance to cholinesterase-inhibiting organophosphates (OP's) the present investigation was focussed on behavioral procedures affecting the development of tolerance. The effects of chronic administration of the OP's DFP (600 micrograms/kg SC) and soman (60 micrograms/kg SC) were compared in rats. These doses do not cause detectable effects upon close observation of the animals. As was found before, behavioral tolerance developed following DFP, but not following soman. Repeated behavioral testing affected the development of tolerance. Cross-tolerance between these two inhibitors was not found. Surprisingly, when DFP was administered 48 hr after soman, all animals were observationally normal, and when soman was given 48 hr after DFP the majority of the animals died. This indicates that the sequence in which these inhibitors were administered was of major importance. It is concluded that practice-related and/or state-dependent factors are important for the development of behavioral tolerance and that one should be careful in making generalizing statements about tolerance to cholinesterase-inhibiting OP's.
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PMID:On the development of behavioral tolerance to organophosphates. III: Behavioral aspects. 233 48

Utilizing a variation of the Fink-Heimer method, we examined the extent and location of axonal and terminal degeneration within the chicken cervical spinal cord, brainstem and cerebellum resulting from a single subcutaneous dose of bis(1-methylethyl)phosphorofluoridate (DFP). The effects of DFP on the activities of whole-brain neuropathy target esterase (NTE) and cholinesterase (ChE) were also assessed as were the development and severity of clinical signs characteristic of organophosphorus-induced delayed neuropathy (OPIDN). Both whole brain NTE and ChE activities were maximally inhibited during the first 24 h post-exposure, showing gradual recovery over a period of 3 weeks. OPIDN clinical signs were not observed at 7 days post-DFP but progressed to severe ataxia by day 14 and paralysis by day 21. There was a relative absence of degeneration at 7 days, a dramatic increase in degeneration density at 14 days, and high density degeneration at both 21 and 28 days. Cervical spinal and medullary tracts containing axonal degeneration included the fasciculus gracilis, dorsal and ventral spinocerebellar tracts, spinal lemniscus, and the intramedullary portions of the glossopharyngeal and vagus nerves. Brainstem nuclei containing terminal degeneration included the lateral cervical, gracile-cuneate, external cuneate, and inferior olivary nuclei, the nucleus tractus solitarius, and the lateral and paragigantocellular lateral reticular nuclei. Mossy fiber degeneration was also present in cerebellar folia I-Vb. These results show that exposure to DFP causes axonal and terminal degeneration in ascending spinal tracts, brainstem nuclei and cerebellar folia associated with the transmission of somatic and visceral sensory information.
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PMID:Selective axonal and terminal degeneration in the chicken brainstem and cerebellum following exposure to bis(1-methylethyl)phosphorofluoridate (DFP). 239 6

Neurotoxicity of diisopropyl phosphorofluoridate (DFP) was examined at 85 weeks of age in hens of two lines selected for high (HA) and low (LA) antibody response to sheep erythrocytes. DFP was administered by subcutaneous injection in doses of 0.25, 0.50 and 1.00 mg/kg and hens were observed for cholinergic signs at 30 min and for delayed neuropathy 8 to 14 days post-administration. Toxicity to DFP increased in severity with the dose and genetic differences were present because hens of line HA were more sensitive to DFP than were those of line LA. HA hens also had lower A-esterase activities and higher heterophil-to-lymphocyte ratios. No line x treatment interaction was evident, however, for activities of neurotoxic esterase or brain cholinesterase measured 24 hr after DFP administration.
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PMID:Differences in response of chickens from two genetic lines to diisopropyl phosphorofluoridate. 254 74

The effect of chronic treatment with anethole trithione (ANTT) on the phosphatidylinositol (PI) turnover and cyclic (c)AMP and cGMP accumulation in rat submaxillary glands (SMG) has been compared with the effect of chronic treatment with atropine and a cholinesterase inhibitor, diisopropylfluorophosphate (dyflos, DFP). Experiments were performed 24, 48 and 24 h after the last dose of ANTT, atropine and dyflos, respectively. ANTT and atropine enhanced carbachol-stimulated [32P] incorporation into phosphatidic acid in the SMG slices, while dyflos showed no effect. Pilocarpine-stimulated in-vivo incorporation of [3H]myoinositol into inositol phosphates was significantly enhanced by ANTT, but not by atropine or by dyflos. Phospholipase C-dependent hydrolysis of phosphatidylinositol 4,5-bisphosphate was significantly enhanced by ANTT and atropine, but not by dyflos. Pilocarpine-stimulated in-vivo accumulation of cAMP and cGMP was enhanced by ANTT and atropine, but dyflos reduced cAMP accumulation without affecting cGMP accumulation. The enhancement of PI turnover and cyclic nucleotide accumulation seems to contribute to the development of supersensitivity of the salivary gland caused by chronic treatment with ANTT and atropine, while reduction of cAMP accumulation may be responsible for the subsensitivity caused by dyflos.
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PMID:Enhancement of phosphatidylinositol turnover and cyclic nucleotide accumulation by chronic anethole trithione treatment in rat submaxillary glands. 256 64


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