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)

This paper describes studies aimed at determining the acute anticholinergic and delayed neurotoxic potential of the organophosphate insecticide pirimiphos-methyl (O-2-diethylamino-6-methylpyrimidin-4-yl O,O-dimethyl phosphorothioate) in the hen. Delayed neuropathy was assessed by biochemical measurement of neuropathy target esterase (NTE) activities in the brain and spinal cord, clinical signs of neuropathy over two 21-day periods and histological assessment of nervous tissue. Acetylcholinesterase (AChE) activity was also determined in the brain and spinal cord. Hens were given a single oral dose of 100 mg kg-1 pirimiphos-methyl, which was followed by a repeated dose after 21 days. Tri-o-cresyl phosphate (TOCP), 500 mg kg-1, was used as a positive control. All pirimiphos-methyl-treated hens received prophylactic doses of N-methylpyridinium-2-aldoxime methanesulphonate (P2S) and atropine sulphate. Hens dosed with pirimiphos-methyl had very low AChE activities (less than 20% of control) in both the brain and spinal cord, 24 and 48 h after dosing. In the TOCP-treated hens, the activities were about 90% of control. NTE activities in the brain and spinal cord of pirimiphos-methyl-treated hens were identical to those in the controls, while they were profoundly inhibited (greater than 80%) in the TOCP-treated hens. All hens dosed with pirimiphos-methyl showed the expected signs of AChE inhibition and, following recovery, usually by Day 5, no clinical signs of delayed neuropathy were seen. The TOCP-treated hens developed clinical signs of neuropathy.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Delayed neuropathy and acute toxicity studies with pirimiphos-methyl in the hen. 233 8

Some organophosphorus compounds (OP) induce a delayed polyneuropathy (OPIDP) which is initiated by the phosphorylation of the so-called neuropathy target esterase (NTE). In this work some aspects of hen sciatic nerve NTE are studied. The assay method is reported and modifications are discussed and a combined method proposed. Proximo-distal distribution showed a significant difference from proximal (100 +/- 10%) to distal (69 +/- 9%) fragments, in accordance with reported data. The time course of in vivo regeneration after a single TOCP dose (200 mg/kg, post oral) showed some differences when compared with hen brain NTE. Sciatic nerve NTE showed a delay of 2-3 days before regeneration but then regenerated faster (74% activity at day 7) than brain NTE (50% activity at day 7). A slower rate of regeneration of distal than proximal segments has been suggested to explain higher sensitivity of distal segments [3], however in this work no significant differences were observed in the rate of regeneration when comparing proximal and distal fragments.
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PMID:Sciatic nerve neuropathy target esterase. Methods of assay, proximo-distal distribution and regeneration. 337 20

Simultaneous intoxication with hexacarbon solvents and organophosphorus compounds has been considered a possible critical factor in some occupational neuropathies and their interactions proved to cause potentiation effects in hens [1-3]. A high degree of inhibition of neuropathy target esterase (NTE) is needed to develop organophosphorus induced polyneuropathy (OPIDP). In this work, the inhibition of NTE, BuChE and AChE by TOCP on control and n-hexane pretreated (7-15 days, 300 mg/kg per day) hens is studied. Using a single TOCP dose of 200 mg/kg, n-hexane pretreated hens showed synergistic effects, but no significant differences were observed in the inhibition of cholinesterases and NTE in brain or spinal cord. With lower TOCP dose (20 mg/kg) statistically significant differences were observed, which were not drastic but could be important because they involved an increase of inhibition up to critical threshold values (from 40-50% to 60-70% inhibition). However, no clinical effects were observed in these animals. Possible mechanisms of neurotoxic interaction are discussed.
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PMID:Low non-neuropathic tri-o-cresyl phosphate (TOCP) doses inhibit neuropathy target esterase near the neuropathic threshold in n-hexane pretreated hens. 337 28

The mechanism of delayed neurotoxicity of some OP (organophosphorus) esters such as DFP (di-isopropyl phosphorofluoridate) and TOCP (tri-o-cresyl phosphate) involves an initial two-step process affecting an esterase called NTE (neurotoxic esterase). This understanding permits the assessment of delayed neuropathic potential in terms of a quantitative measurement of inhibition of NTE in tissue taken from dosed hens. Structure/activity relationships have been rationalized and the neurotoxic potential of those OP esters which are direct inhibitors of esterases may now be assessed in vitro. The response of human NTE can usefully be compared with that of hen NTE. Nil delayed neurotoxic potential is associated with carbamate or phosphinate anticholinesterases which may be designed as insecticides.
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PMID:The mechanism of delayed neuropathy caused by some organophosphorus esters: using the understanding to improve safety. 700 90

Inhibition of neuropathy target esterase (NTE, neurotoxic esterase) and acetylcholinesterase (AChE) activities was compared in brain and spinal cords of adult While Leghorn hens and adult male Long Evan rats 4-48 hr after administration of triortho-tolyl phosphate (TOTP po, 50-500 mg/kg to hens; 300-1000 mg/kg to rats), phenyl saligenin phosphate (PSP im 0.1-2.5 mg/kg to hens; 5-24 mg/kg to rats), mipafox (3-30 mg/kg ip to hens and rats), diisopropyl phosphorofluoridate (DFP sc, 0.25-1.0 mg/kg to hens; 1-3 mg/kg to rats), dichlorvos (5-60 mg/kg ip to hens; 600-2000 mg/kg to rats), and carbaryl (300-560 mg/kg ip to hens; 30-170 mg/kg to rats). Inhibitions of NTE and AChE were dose-related after administration of all compounds to both species. Hens and rats given TOTP, PSP, mipafox, and DFP demonstrated delayed neuropathy 3 weeks later, with spinal cord lesions and clinical signs more notable in hens. Ratios of NTE/AChE inhibition in hen spinal cord, averaged over the doses used, were 2.6 after TOTP, 5.2 after PSP, 1.3 after mipafox, and 0.9 after DFP, which contrast with 0.53 after dichlorvos, 1.0 after malathion, and 0.46 after carbaryl. Rat NTE/AChE inhibition ratios were 0.9 after TOTP, 2.6 after PSP, 1.0 after mipafox, 0.62 after DFP, 1.3 after dichlorvos, 2.2 after malathion, and 1.1 after carbaryl. The lower NTE/AChE ratios in rats given dosages of the four organophosphorus compounds that caused delayed neuropathy interferred with survival, an effect that was not a problem in hens.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Comparison of the relative inhibition of acetylcholinesterase and neuropathy target esterase in rats and hens given cholinesterase inhibitors. 771 47

This study compares two direct-acting neuropathy target esterase (NTE) inhibitors (mipafox and 2-octyl-4H-1,3,2-benzodioxophosphorin 2-oxide (OBDPO)), a metabolic precursor to an NTE inhibitor (tri-o-cresyl phosphate or TOCP) and a potent acetylcholinesterase inhibitor (chlorpyrifos oxon or CPO) for their effects on outgrowth of neurite-like and cell processes and on viability in differentiated cultured cells (rat adrenal pheochromocytoma (PC-12) and brain glial tumor (C6)). The direct-acting NTE inhibitors block process outgrowth by 50% or more at 50-100 microM for OBDPO and 100-200 microM for mipafox, well below their cytotoxic levels (EC50 values, 445-474 microM for OBDPO and 1021-1613 microM for mipafox). In contrast, the effects on process development for TOCP and CPO parallel their cytotoxicity. These findings suggest that inhibition of neurite-like and cell process outgrowth by OBDPO and mipafox may be associated with NTE inhibition.
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PMID:Organophosphorus neuropathy target esterase inhibitors selectively block outgrowth of neurite-like and cell processes in cultured cells. 978 82

Delayed neuropathy and inhibition of soluble neuropathy target esterase (NTE) and acetylcholinesterase (AChE) activities in different regions of brain and spinal cord of adult hens were studied after the intravenous administration of leptophos (30 mg/kg), tri-o-cresyl phosphate (TOCP 40 mg/kg) or dipterex (200 mg/kg). The level of NTE activity varied according to the regions of the central nervous system (CNS) of the control (normal) hen, being higher in the cerebrum (74.1 micromol of phenyl valerate hydrolyzed/10 minutes/mg protein) and in the cerebellum (68.7), and lower in the spinal cord (44.5 in cervical, 55.6 in thoracic and 50.0 in lumbar cord). Hens given leptophos and TOCP demonstrated delayed neuropathy with obvious inhibition of NTE, but the times of onset and the degrees of peak inhibition of NTE activity were different: 6-24 hours after dosing and 73-82% of normal activity for leptophos, and 24-48 hours and 45-80% for TOCP, respectively. Furthermore, the average inhibition of NTE during 6-48 hours after dosing, (called here 'period average inhibition') was also significantly different between the leptophos group (63-73%) and TOCP group (40-64%). Hens given dipterex did not demonstrate delayed neuropathy, and had the least peak inhibition and period average inhibition of NTE activity among the 3 groups. Ratios of NTE inhibition/AChE inhibition were higher in the leptophos group (0.91-1.24) and TOCP group (1.13-2.45) than in the dipterex group (0.25-0.79). These results indicate that the distribution of NTE in the soluble fraction of membrane proteins is different in different regions of the CNS, and that the degree of peak inhibition of NTE activity and the time of onset of peak inhibition induced by organophosphorus compounds (OPs) also differ for different OPs. Thus, practical and useful NTE measurements should identify the peak inhibition and period inhibition in several nervous tissue regions.
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PMID:Delayed neuropathy and inhibition of soluble neuropathy target esterase following the administration of organophosphorus compounds to hens. 982 77

An animal (rat) model of chronic stress (corticosterone in the drinking water) was used to study the interaction of stress and the organophosphorus (OP) neurotoxicants chlorpyrifos (60 mg/kg subcutaneously in a single dose) and tri-ortho-tolyl phosphate (TOTP, at 75, 150, or 300 mg/kg given 7 times orally in a 2-wk period). Adult male Long-Evans rats were provided with corticosterone in drinking water (400 microg/ml, w/v) for a total of 28 d, which led to significantly decreased weight and decreased cellularity of the thymus and spleen. Seven days after initiation of corticosterone treatment, half of the rats were given chlorpyrifos, and an additional 7 d later the 2-wk, 7-dose treatment of TOTP was initiated. During the 28-d test period, behavior of rats was evaluated using a functional observational battery (FOB), motor activity, and passive avoidance. Reductions in body weight, grip strength, and ambulatory movements occurred as a result of corticosterone treatment. Decreased body weight and grip strength were also elicited by TOTP, and the interactions of corticosterone and TOTP enhanced the effects on body weight and grip strength. Blood cholinesterase levels were obtained during the 28-d study period and found useful for monitoring OP exposure. At the end of the 28-d testing period, rats were sacrificed and activities of cholinesterase, neurotoxic esterase (neuropathy target esterase), and/or carboxylesterase were evaluated in blood, liver, and/or brain regions (basal forebrain, caudate putamen, cerebral cortex, hippocampus). All these esterases in brain were inhibited in a dose-related manner by TOTP, with some enhancement in rats drinking corticosterone-containing water. In addition, choline acetyltransferase, glial acidic fibrillary protein (GFAP), glutathione peroxidase, and superoxide dismutase were evaluated in one or more of the brain regions already identified. Choline acetyltransferase, glutathione peroxidase, and superoxide dismutase activities were unaffected by treatments. However, GFAP was elevated above control levels in the cerebral cortex of rats by all treatments (corticosterone, chlorpyrifos, TOTP). Neuropathological examination revealed early stages of dose-related increased distal myelinated fiber axonal degeneration seen in the medullary fasciculus gracilis at only the highest dose of TOTP (300 mg/kg).
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PMID:Neurologic and immunologic effects of exposure to corticosterone, chlorpyrifos, and multiple doses of tri-ortho-tolyl phosphate over a 28-day period in rats. 1471 79

To examine the efficacy of calcium gluconate (two doses of Ca-Glu 5 mg/kg i.v.) to alleviate the injurious effects of organophosphorus induced delayed neuropathy (OPIDN) in the presence or absence of phenylmethanesulfonyl fluoride (PMSF 90 mg/kg i.m.), 14 groups of four isabrown hens were used. To measure the lymphocyte neuropathy target esterase (LNTE)activity, groups receiving just distilled water (control), groups receiving just Tri-orto-cresyl phosphate (TOCP; 500 mg/kg p.o.) (Positive control), and other groups receiving TOCP and Ca-Glu or PMSF simultaneously or 12 hours later following intoxication by TOCP were used. They were sacrificed 12 and 24 hours after the administration of TOCP. To observe a 28-day time course of neurotoxicity scores and calcium plasma concentration, five groups were used. Regarding free Ca(2+)in the plasma, the positive control produced a characteristic profile time course up and down during 28 days, and some hens with maximum score of neurotoxicity in 28 days. The treatment, which prevented greater oscillation in free Ca(2+) in the plasma, presented a decrease in OPIDN in relation to the positive control. Twelve hours after the administration of TOCP, LNTE was 70-80% inhibited when compared with control, whereas the first decrease in the free Ca(2+) in the plasma was significantly different from the control only 24 hours after the administration of TOCP. In summary, the sooner the Ca-Glu is started, the less severe the neuropathy effects.
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PMID:Effects of calcium gluconate and PMSF in the treatment of acute intoxication of chicken by TOCP. 1865 Feb 57

Organophosphorus (OP) used as pesticides and hydraulic fluids can produce acute poisoning known as OP-induced delayed neuropathy (OPIDN), whose effects take long time to recover. Thus a secure therapeutic strategy to prevent the most serious effects of this poisoning would be welcome. In this study, tri-o-cresyl phosphate (TOCP, 500 mg/kg p.o.) was given to hens, followed or not by nimodipine (1mg/kg i.m.) and calcium gluconate (Ca-glu 5mg/kg i.v.). Six hours after TOCP intoxication, neuropathy target esterase (NTE) activity inhibition was observed, peaking after 24h exceeding 80% inhibition. A fall in the plasmatic calcium levels was noted 12h after TOCP was given and, in the sciatic nerve, Ca(2+) fell 56.4% 24h later; at the same time calcium activated neutral protease (CANP) activity increased 308.7%, an effect that lasted 14 days. Any bird that received therapeutic treatment after TOCP intoxication presented significant signs of OPIDN. These results suggest that NTE may be implicated in the regulation of calcium entrance into cells being responsible for the maintenance of normal function of calcium channels, and that increasing CANP activity is responsible to triggering OPIDN. Thus, with one suitably adjusted dose of nimodipine as well as Ca-glu, we believe that this treatment strategy may be used in humans with acute poisoning by neuropathic OP.
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PMID:Organophosphorus-induced delayed neuropathy: a simple and efficient therapeutic strategy. 1991 63


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