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)

The serine/cysteine hydrolase inhibitor phenylmethylsulfonyl fluoride (PMSF) markedly intensifies the clinical expression of organophosphorus-induced delayed neurotoxicity (OPIDN) in adult chickens when administered after organophosphate exposure. In this study, we have examined the ability of PMSF post-treatment to affect sensitivity to OPIDN in developing animals at ages normally showing resistance. Chickens (35, 49 or 70 days of age) were treated with diisopropylphosphorofluoridate (DFP, 2 mg/kg, sc) and then treated four hours later with PMSF (90 mg/kg, sc) or vehicle only and examined for clinical signs of ataxia and incoordination. Chickens treated with DFP alone showed a marked age-related increase in the severity of motor deficits. Birds treated with DFP followed by PMSF showed more extensive clinical deficits relative to those treated with DFP only, but relatively similar degrees of motor dysfunction among the age groups. Cervical spinal cord samples processed by the Fink-Heimer degeneration method indicated that PMSF post-treatment induced more extensive axonal degeneration in all age groups relative to treatment with DFP only. As the DFP treatment alone caused greater than or equal to 90% inhibition of neurotoxic esterase activity (NTE, the putative molecular target site for OPIDN), interaction with NTE by PMSF does not appear to be involved in potentiation. We hypothesize that PMSF potentiates OPIDN through impairment of a physiological process which normally imparts resistance to young animals and which regresses during development.
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PMID:Phenylmethylsulfonyl fluoride alters sensitivity to organophosphorus-induced delayed neurotoxicity in developing animals. 143 55

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

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

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

Some organophosphorous esters cause a polyneuropathy which becomes clinically evident 2 weeks after a single dose. The pathogenesis involves modifications of a target protein, neuropathy target esterase, in the axons and a selective inhibition of retrograde axonal transport. It was suggested that copper metabolism might also be involved because of increased levels of plasma copper and ceruloplasmin in animals developing this polyneuropathy. Our results do not confirm this observation; treatment of hens with highly neuropathic single doses of two organophosphates (dihexyl-2,2-dichlorovinyl phosphate and mono-o-cresyl diphenyl phosphate) does not affect total and plasma free copper when measured several times during the development of polyneuropathy. We concluded that copper homeostasis is not affected and that copper changes are unlikely to be involved in the pathogenesis of this polyneuropathy.
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PMID:Blood copper in organophosphate-induced delayed polyneuropathy. 283 31

The development of organophosphorus-induced delayed neurotoxicity (OPIDN) was studied in the European ferret (Mustela putorius furo). A single oral or dermal dose of 250, 500, or 1000 mg tri-o-tolyl phosphate (TOTP)/kg body weight was administered to adult male ferrets. Corn oil served as the vehicle in the oral test and 95% ethanol was the vehicle in the dermal test. At 48 h posttreatment, half the animals in each group were killed by cervical dislocation for assessment of whole-brain neuropathy target esterase (NTE) activity. The remaining 5 animals per group were observed and examined neurologically on a daily basis for a subsequent 54 d. All ferrets dosed dermally with 1000 mg TOTP/kg body weight developed clinical signs characteristic of OPIDN ranging from ataxia to partial paresis. Ferrets administered 250 and 500 mg TOTP/kg body weight via the dermal route displayed variable degrees of hind limb weakness and ataxia. Of the animals dosed orally, only those in the 1000 mg TOTP/kg body weight group showed clinical signs indicative of OPIDN. These signs did not progress beyond mild ataxia. Small amounts of axonal degeneration were noted in the dorsolateral part of the lateral funiculus and in the fasciculus gracilis of spinal cords in ferrets receiving dermal doses of 1000 mg TOTP/kg body weight. Whole-brain neuropathy target esterase activity was also maximally inhibited (46%) in animals receiving 1000 mg TOTP/kg dermally. These results suggest that the ferret is a species that is susceptible to OPIDN.
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PMID:Delayed neurotoxic effects of tri-o-tolyl phosphate in the European ferret. 291 34

Cyclic phenyl saligenin phosphate (PSP) proved to be a potent delayed neurotoxin, eliciting clinical disease and lesions, and depressing neuropathy target esterase and plasma cholinesterase at much lower doses than the protoxicant tri-ortho-tolyl phosphate (TOTP). Using adult White Leghorn chickens, we noted qualitative similarities in clinical signs and peripheral nerve and spinal cord lesions elicited by PSP and the TOTP. Ataxia and weakness were prominent clinical effects. Lesions began as a distal axonopathy affecting larger myelinated fibers in spinal cord white matter and peripheral nerve. The latter were studied in detail. Major features of the lesion were intra-axonal collections of mitochondria, dense and lamellar bodies, and granular degeneration of neurofilaments. These led to Wallerian-like degeneration. Percentages of teased peripheral nerve fibers demonstrating such degeneration correlated with severity of clinical signs.
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PMID:Neuropathological effects of phenyl saligenin phosphate in chickens. 360 Dec 42

Human and animal eosinophils contain a powerful neurotoxin that causes selective neuronal and axonal damage to white matter of cerebellum and spinal cord of experimental animals when injected intrathecally. This reaction is termed the "Gordon phenomenon." We purified the eosinophil-derived neurotoxin from eosinophil-rich leukocyte suspensions or eosinophil granules from four patients with various hypereosinophilic syndromes. A single protein with an average molecular weight of 18,400 was isolated by sequential chromatography on Sephadex G-50 columns and analyzed by sodium dodecyl sulfate/polyacrylamide gel electrophoresis of column fractions. The purified eosinophil-derived neurotoxin from the cells of these patients retained the potent neurotoxic activity of the crude eosinophil or eosinophil granule extracts in experimental animals. These animals developed the syndrome of stiffness and ataxia progressing to severe paralysis characteristic of the Gordon phenomenon. Histologic examination of the brains of animals injected with purified eosinophil-derived neurotoxin confirmed the characteristic widespread loss of Purkinje cells and severe spongiform vacuolation in the white matter of cerebellum, brain stem, and spinal cord. We have established the location of eosinophil-derived neurotoxin in the eosinophil granule and have shown that it is distinct from several other eosinophil proteins, the granule major basic protein, and the Charcot-Leyden crystal protein (lysophospholipase).
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PMID:Purification of human eosinophil-derived neurotoxin. 694 62

A "hen model" or organophosphorus induced delayed neuropathy (OPIDN) has been developed using white leghorn exposed acutely to one of five dosages of tri-ortho-cresyl phosphate (TOCP), between 300 to 700 mg/Kg. Neuropathy target esterase was studied in brain and peripheral nerve 24 and 48 hrs following exposure. Behavioral symptoms abnormality was assessed from days 1 through 20 after exposure using a 7 point rating scale and neuropathological examination was conducted on sample collected from animals on days 0, 7, 14 and 21. Neuropathological abnormalities were indicated by damage scores between 0 (no damage) and 4 (gliosis of brain tissue, myelin loss, appearance of axonal foci etc and more than 55% degeneration of peripheral nerve fibres). TOCP (600 and 700 mg/Kg, orally) was able to inhibit NTE more than 75% in brain and peripheral nerves. TOCP at the same dosage was also capable of resulting maximal levels of neuropathological score at 4. After exposure to doses weight loss was observed abruptly in a greater extent at the beginning leading to a change in weight gain till the end of the experiment. Behavioral signs were also dose dependent. Symptoms (gain abnormality, ataxia, paresis) were noted on the early stage of experiment. Inhibition of NTE was 65% could not be reached in hens given TOCP without causing lethality and no significant ataxia or lesions developed in those birds. Behavioral signs were also observed to be late onset. These data indicate that more than 75% inhibition of peripheral nerve NTE after 24 hr exposure was predictive of severe behavioral abnormalities and pathology in the hen whereas less peripheral NTE inhibition was indicative of less severe behavioral abnormalities and a lower score for neuropathological damage.
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PMID:Biochemical, neuropathological and behavioral studies in hens induced by acute exposure of tri-ortho-cresyl phosphate. 755 52


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