Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.1.5 (neuropathy target esterase)
1,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Indices of organophosphorus (OP)-induced delayed neuropathy (OPIDN) in the hen model have traditionally been restricted to the early inhibition of neuropathy target esterase (NTE) and ataxia with associated pathological changes in hind limb peripheral nerve which occur more than 7 days after OP exposure. The biventer cervicis nerve-muscle preparation was used to evaluate OPIDN in adult hens at various time periods after treatment with either the protoxicant tri-o-tolyl phosphate (TOTP), 360 mg/kg po, or the active congener phenyl saligenin phosphate (PSP), 2.5 mg/kg im. NTE activity was 21 and 48% of control for TOTP and PSP, respectively, 4 days after administration. Clinical signs were notable by 10 days and progressed in severity to paralysis by 21 days. Partial clinical recovery was evident at 37 days. Denervation hypersensitivity of biventer cervicis muscle to acetylcholine (ACh) was evident as early as 4 days following TOTP or PSP treatment. The sensitivity to ACh was greatest 21 days after OP administration, with partial recovery at 37 days. Strength-duration curves (SDC) of preparations from OP-treated hens showed an increase in excitability thresholds and elevated rheobase with shorter chronaxie than did preparations from controls as early as 4 days following treatment with either compound. SDC at 37 days indicated partial reinnervation. Peripheral nerve myelinated fiber degeneration and regeneration consistent with these physiological changes was seen on histopathological examination. This study suggests that the biventer cervicis nerve-muscle preparation may prove useful for detection of functional and morphological changes that occur during the interval between NTE inhibition and appearance of clinical deficits.
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PMID:Use of the biventer cervicis nerve-muscle preparation to detect early changes following exposure to organophosphates inducing delayed neuropathy. 237 92

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

The induction of central-peripheral distal axonopathy in hens singly dosed with some organophosphorus (OP) compounds, such as di-n-butyl-2,2-dichlorovinyl phosphate (DBDCVP), requires greater than 80% organophosphorylation and subsequent intramolecular rearrangement ("aging") of a protein [neuropathy target esterase (NTE)] in the axon. Suprathreshold biochemical reaction, 24 h after dosing with DBDCVP (0.75-1.00 mg/kg s.c.), is shown to be associated with progressive decrement of retrograde axonal transport in sensory and motor fibers. The maximum transport deficit (about 70% reduction) is reached 7 days after DBDCVP, prior to the appearance of axonal degeneration and the onset of clinical signs of neuropathy (day 10-11). By contrast, phenylmethylsulfonyl fluoride (30 mg/kg s.c.), an agent that prevents the development of OP neuropathy by inhibiting NTE without the "aging" reaction, had no effect on axon transport, nerve fiber integrity, or clinical status and, when administered prior to a neurotoxic dose of DBDCVP (1.00 mg/kg s.c.), prevented DBDCVP effects. Paraoxon (0.2 mg/kg s.c.) neither inhibited NTE nor caused deficits in retrograde transport or neuropathy. Taken in concert, these studies demonstrate that induced deficits in retrograde transport are associated with the pathogenesis of OP-induced nerve-fiber degeneration and the threshold-initiating mechanism thereof.
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PMID:Progressive deficit of retrograde axonal transport is associated with the pathogenesis of di-n-butyl dichlorvos axonopathy. 244 71

The interaction in vivo of four O-alkyl O-2,5-dichlorophenyl phosphoramidates with neural neuropathy target esterase (NTE) and acetylcholinesterase (AChE) and their ability to cause delayed polyneuropathy in hens has been examined. Previous studies in vitro (Vilanova, Johnson & Vicedo, Pestic. Biochem. Physiol., 28 (1987) 224) had led to the prediction that these compounds would not be neuropathic but, rather, would be prophylactic agents against organophosphorus-induced delayed polyneuropathy. In vivo the effects of these esters on the enzymes differ in 2 respects from effects in vitro: (i) Relative sensitivity of the enzymes was different: thus greater than 50% of brain NTE remained 24 h after an oral dose of 15 mg/kg of the n-hexyl ester while only 10-30% of AChE remained although NTE was the more sensitive enzyme in vitro; (ii) In no case could the inhibited NTE or AChE in autopsy samples from birds dosed with any of the 4 esters be reactivated by treatment with potassium fluoride in vitro: the inhibited enzymes produced by incubation of tissue with the esters in vitro had been reactivatable. Prophylaxis, with therapy in some cases, was required to prevent acute anticholinesterase poisoning when doses were sufficient to cause high inhibition of neural NTE. Inhibition in brain was typically 5-10% more than in spinal cord and 10-15% more than in sciatic nerve. Unambiguous signs of polyneuropathy (Grade 3 or more on an 8-point scale) were not seen in birds observed up to 3 weeks after doses which caused less than 70% inhibition of NTE in brain and spinal cord or less than 60% inhibition in sciatic nerve of pair-dosed birds assayed 24 h after dosing. Doses of 300, 10, 100 and 65 mg/kg, respectively, of the methyl, ethyl, n-butyl and n-hexyl esters caused greater than 70% inhibition of NTE in all 3 neural tissues and neuropathy in the majority of observed birds. Analysis of consolidated dose/response data from 36 assayed and 51 observed birds showed that effects of Grade 3 or more were produced in about 90% of birds when inhibition of NTE was greater than 90% in brain, greater than 85% in spinal cord or greater than 75% in sciatic nerve.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Biochemical and clinical tests of the delayed neuropathic potential of some O-alkyl O-dichlorophenyl phosphoramidate analogues of methamidophos (O,S-dimethyl phosphorothioamidate). 253 70

The effect of the microsomal enzyme inducer beta-naphthoflavone (beta NF) on the development of organophosphorus-induced delayed neuropathy (OPIDN) was examined in two laboratories (VPI and MSU), utilizing two strains of White Leghorn hens. A single intraperitoneal injection of beta NF at 80 mg/kg body weight 48 h prior to administration of o-tolyl saligenin phosphate (TSP), the neuroactive metabolite of tri-o-tolyl phosphate (TOTP), caused a significant increase in hepatic microsomal cytochrome P-450 concentrations and aniline hydroxylase activities after 72 h in both strains. Hepatic carboxylesterase and cholinesterase activities were not affected by beta NF treatment in either strain. Administration of TSP in single subcutaneous doses of 20 and 25 mg/kg body weight (VPI) or 30 and 60 mg/kg body weight (MSU) caused significant inhibition of whole-brain neuropathy target esterase (NTE) activity 24 h postdosing, and hens subsequently developed clinical signs characteristics of OPIDN. beta NF had no significant effect on NTE inhibition or on initiation or severity of OPIDN clinical signs. However, OPIDN clinical signs were less severe in the strain of bird (MSU) with the higher intrinsic hepatic carboxylesterase activity and the higher beta NF-induced cytochrome P-450 concentration. The study indicates that microsomal enzyme induction, which has been shown to alleviate TOTP-induced delayed neuropathy, could not alleviate OPIDN resulting from exposure to TSP. This study also suggests that strain may affect susceptibility to TSP-induced delayed neuropathy.
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PMID:Effect of beta-naphthoflavone on o-tolyl saligenin phosphate-induced delayed neuropathy in two lines of chickens. 259 76

Organophosphate-induced delayed polyneuropathy (OPIDP) is initiated by inhibition/aging of more than 70-75% of neuropathy target esterase (NTE). Di-n-butyl-2,2-dichlorovinyl phosphate (DBDCVP) (1 mg/kg s.c.) inhibited 96%, 86% and 83% of NTE in brain, spinal cord and peripheral nerve, respectively, and induced a typical central peripheral distal axonopathy in hens. A lower dose (0.45 mg/kg s.c.) caused 90%, 83% and 54% NTE inhibition in the same organs; by contrast, hens developed a spastic ataxia with axonal degeneration in spinal cord but not in peripheral nerve. With a dose of 0.2 mg/kg s.c., a suprathreshold inhibition of NTE was produced in brain (78%) but not in spinal cord (56%) and peripheral nerve (33%) and no morphological or clinical signs of neuropathy developed in hens. With doses up to 4.0 mg/kg s.c., acetylcholinesterase (AChE) inhibition was similar throughout the nervous system. In vitro time-course inhibition studies showed a different sensitivity to DBDCVP of NTE from peripheral nerve (ka = 5.4 x 10(6)) relative to that from spinal cord (ka = 13.9 x 10(6)) or brain (ka = 20.6 x 10(6)). In vitro I50s of DBDCVP for AChE were similar in brain, spinal cord and peripheral nerve (11-17 nM). These data support the hypothesis that the critical target for initiation of OPIDP is located in the nerve fiber, possibly in the axon and also suggest that peripheral nerve NTE has a different sensitivity to DBDCVP than the brain enzyme.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:In vivo and in vitro regional differential sensitivity of neuropathy target esterase to di-n-butyl-2,2-dichlorovinyl phosphate. 261 60

To estimate the potential of small doses of sarin (types I and II) and soman to cause delayed neuropathic effects, 400, 200, 61, and 0 micrograms/kg of sarin-I, 280, 140, 70, and 0 micrograms/kg of sarin-II, and 14.2, 7.1, 3.5, and 0 micrograms/kg of soman by gavage were compared with 510 mg/kg tri-o-cresyl phosphate (TOCP) in 14- to 18-month-old SPF white leghorn hens (4/dose) protected with atropine (100 mg/kg). The neuropathy target esterase (NTE) activity 24 hr after dosing was determined in brain, spinal cord, and lymphocytes and in plasma and brain for cholinesterase and carboxylesterase. None of the compounds showed statistically significant NTE decreases. Sarin-II showed a dose-related trend in the lymphocyte NTE (to 33% of control at 280 micrograms/kg), suggesting that longer exposure to lower doses might cause a cumulative neurotoxic insult. All of the agents decreased the activity of plasma and brain cholinesterase and carboxylesterase. Using more than 70% inhibition of brain NTE as a biochemical predictor of delayed neuropathy, sarin and soman appear unable to cause delayed neuropathy at nonlethal doses within this protocol.
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PMID:Neuropathy target esterase in hens after sarin and soman. 276 93

Neurotoxic esterase (neuropathy target enzyme, NTE) is an enzyme whose irreversible inhibition is the apparent first step in the induction of organophosphorus-induced delayed neuropathy. NTE is an integral membrane protein and thus must be solubilized before isolation can be attempted. This study describes solubilization of active chicken brain NTE with the nondenaturing detergent 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS) and characterization of the detergent-solubilized enzyme by gel exclusion chromatography. When detergent-solubilized membranes were chromatographed on Sepharose gel exclusion media, NTE activity eluted with an apparent molecular weight of 880-970 kD. When [3H]diisopropylphosphorofluoridate-radiolabeled membranes and unlabeled microsomal membranes were CHAPS-solubilized, combined and chromatographed on Sepharose 4B, NTE activity coeluted with two radiolabeled proteins (Mr = 148 kD and Mr = 112 kD using sodium dodecyl sulfate-polyacrylamide gel electrophoresis with reducing conditions). Another radiolabeled protein (Mr = 92 kD) coeluted exclusively with inhibitor-resistant esterase activity. This study provides strong evidence that the 148 and 112 kD proteins are subunits of a multicomponent NTE complex.
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PMID:Chromatographic characterization of neurotoxic esterase. 291 Feb 99

Assay of neuropathy target esterase (NTE) which accounts for about 70% of paraoxon-resistant phenyl valerate (PV) esterase activity of hen brain depends on the fact that it is selectively inhibited by mipafox. A previous study of structure/activity relationships (Biochem. Pharmac. 24, 797, 1975) has been extended. Among 14 potential substrates NTE hydrolysed phenyl phenoxyacetate and phenyl thiophenoxyacetate faster (1.5-1.7X) than PV, but selectivity of these substrates for NTE among the paraoxon-resistant esterases was only 35-52%. Seventy-seven other potential inhibitors (organophosphates, phosphonates, phosphoramidates, phosphinates and carbamates) were examined to determine I50NTE and effects on both NTE and "non-NTE" at 3-4 x I50NTE (I 85-95) and, where possible, at 6-20 X I50NTE. Hydrophophic inhibitors with small/flexible leaving groups were generally very inhibitory: several 2,2-dichlorovinyl phosphates and fluorides were active at low nanomolar concentrations. In the dichlorovinyl phosphate series increasing dialkyl chain length beyond n-pentyl decreased inhibitory power, presumably due to steric hindrance since the methyl/n-decyl ester was 15X more active than di-n-decyl. Chloro-substitution of both ortho-positions of a phenyl leaving group for benzylcarbamates reduced inhibitory power more than 20X but had little effect in a phenyl leaving group of methyl phenylphosphonates where the acyl-leaving group bond is longer and less subject to steric hindrance. N-phenylbenzohydroxamyl benzylcarbamate is 10X more potent than any previously described carbamate against NTE. Among stereo-isomers differences of activity ranged from less than 2- to 15-fold. Only diphenylphosphinyl fluoride appeared to be virtually specific for NTE: at 0.5-1 microM it inhibited ca.92% of NTE and 10-13% of "non-NTE" which is similar to the specificity found for 2,6-dichlorophenyl methyl phenylphosphonate which has been claimed to be specific. Diphenylphosphinyl fluoride has an advantage in that it is easily synthesized and should be protective rather than neuropathic, but it is not stable in store. We cannot repeat experiments purporting to show a substantial proportion of a second isozyme of NTE. However, according to first-order kinetics, concentrations of inhibitor greater than 6 X I50 should inhibit NTE greater than 98% and for 19 out of 26 compounds a residue greater than 3% (limit of precision) was found under these conditions: in nearly every case the quantity was 3-5%. This quantity may not be "true NTE" but it cannot be the target for organophosphate-induced delayed neuropathy since it is resistant to various neuropathic and protective compounds.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Sensitivity and selectivity of compounds interacting with neuropathy target esterase. Further structure-activity studies. 319 Jul 48

Organophosphorus-induced delayed polyneuropathy (OPIDP) is thought to result from organophosphorylation of neuropathy target esterase (NTE; formerly known as neurotoxic esterase), followed by an "aging" of the phosphorylated NTE. Protection against OPIDP should thus be achieved by production of an inhibited but "nonaging" NTE. Inhibited NTE produced in vitro by interaction with any of the four resolved isomers of soman aged negligibly (M. K. Johnson, D. J. Read, and H. P. Benschop, 1985a, Biochem. Pharmacol., 34, 1945-1951). Therefore both unresolved soman and the most inhibitory isomer (C(-)P(+)) were tested in adult hens for effects on NTE and for ability to produce OPIDP. With improved prophylaxis and therapy of acute intoxication, birds survived greater than 100 X LD50 of unresolved soman and did not develop OPIDP. One day after dosing, about half of brain and spinal cord NTE was in an unmodified (unaged) inhibited form; at this time eight survivors were challenged with a neuropathic dose of diisopropyl phosphorofluoridate (DFP). No neuropathy developed in four out of eight birds and mild to moderate signs were seen in the other four. Nine challenge control birds receiving DFP after solvent all developed severe neuropathy. Partial protection was seen in three out of three birds dosed prior to DFP challenge with sufficient C(-)P(+) isomer of soman (1.2 mg/kg sc) to convert about half of the spinal cord NTE to unaged inhibited form. Protection was not related to cholinergic shock. Two birds which survived out of eight pretreated with tabun (12 mg/kg sc) had about as much NTE inhibited as after soman administration but it was all in the modified (aged) inhibited form; these birds were not protected against DFP-induced neuropathy. A limited histopathologic examination showed that typical neurodegenerative lesions were seen only in birds with clear clinical neuropathy.
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PMID:High doses of soman protect against organophosphorus-induced delayed polyneuropathy but tabun does not. 334 Oct 26


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