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:3.1.1.7 (acetylcholinesterase)
28,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A case of 38 year old man who worked with organochlorinated and Parathion during 5 years is reported. His follow-up was up to 2 years. The onset of the disease was characterized by cholinergic signs, headache, loss of weight, trembling, miokimias, fasciculations, ataxia, myotonic phenomena (in hands only) and motor sensitive peripheral polyneuropathy (affecting the lower limbs symmetrically). Low concentrations of blood cholinesterases confirmed the etiology. Myotonic phenomena disappeared spontaneously 6 months after the initial observation. One year later, the concentration of erythrocyte acetylcholinesterase was found to be low and plasma cholinesterase was normal, suggesting that the patient was carrier of a congenital deficiency of acetylcholinesterase. In literature relationship between myotonia and intoxication due to organophosphorus was not found. The whole clinical picture, cholinergic symptoms, transitory phenomena and spontaneous motor activity could be explained by an excess of acetylcholine. Electromyography (EMG) in the first observation showed neuromuscular transmission blocking characterized by deficiency or absence of voluntary activity, unexcitability of fibular nerves, with fibrillations and positive peaks as described previously with Mipafox (another organophosphorus agent). During 2 years of observation numerous end-plates potentials of muscular fibres persisted in the EMG. A progressive increase in voluntary activity showed by unit motor potential of almost normal amplitude and very increased duration was observed. No potentials of reinnervation were noted. The results of EMG were explained as disturbances of neuromuscular transmission associated with moderate signs of denervation. The Eaton-Lambert's test and the stimulation of a single unit motor potential confirmed disorder of neuromuscular synapses. The histochemistry of brachial biceps showed scattered atrophic and angulated type I and II fibres. Teased-fibres preparations showed nerve fibres with B, C, and G alterations as defined by Dyck et al. indicating axonal degeneration. These results were according to velocity of sensitive conduction. The conduction velocity of fibular nerves was strongly delayed during all the evolution indicating serious disorders of motor nerves myelin.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Polyneuropathy caused by parathion: clinical, electrophysiologic and histologic studies of a case]. 665 78

Daily dermal administration for 90 days of 0.01 to 10 mg/kg of O-ethyl O-4-nitrophenyl phenylphosphonothioate (EPN) technical grade (85%) in acetone (0.1 ml) on the unprotected back of the neck produced delayed neurotoxicity. Hens given 2.5 to 10 mg/kg daily doses also received daily doses of atropine sulfate for 5 or 6 days to protect against cholinergic acute toxicity. Severity of the clinical condition depended on the concentration of the daily dermal dose of EPN; i.e., while hens given small doses showed only ataxia, those treated with large doses progressed to paralysis and died. The most consistent histopathologic alteration was the degeneration of axons and myelin in the spinal cord which was identical to that found in positive control hens that received daily dermal doses of 5 or 10 mg/kg tri-o-cresyl phosphate (TOCP). Some of the hens treated daily with the smallest tested dose of EPN (0.001 mg/kg) which did not show clinical signs of delayed neurotoxicity showed equivocal histological changes in the spinal cord. EPN and TOCP treatments had a more profound effect on the activity of plasma butyrylcholinesterase than that of brain acetylcholinesterase (AchE). by contrast O,O,-diethyl O-4-nitrophenyl phosphorothioate (parathion) was more inhibitory to brain AChE. Negative control hens that were treated with 90 daily dermal doses of 1 mg/kg of parathion initially showed leg weakness followed by recovery. A group of hens that received the same volume of acetone (0.1 ml) daily remained normal.
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PMID:Effect of subchronic dermal application of O-ethyl O-4-nitrophenyl phenylphosphonothioate on producing delayed neurotoxicity in hens. 668 63

Chlorpyrifos (CPS; O,O-diethyl 3,5,6-trichloro-2-pyridyl phosphorothionate; Dursban) is a widely used broad-spectrum organophosphorus (OP) insecticide. Because some OP compounds can cause a sensory-motor distal axonopathy called OP compound-induced delayed neurotoxicity (OPIDN), CPS has been evaluated for this paralytic effect. Early studies of the neurotoxicity of CPS in young and adult hens reported reversible leg weakness but failed to detect OPIDN. More recently, a human case of mild OPIDN was reported to result from ingestion of a massive dose (about 300 mg/kg) in a suicide attempt. Subsequent experiments in adult hens (the currently accepted animal model of choice for studies of OPIDN) showed that doses of CPS in excess of the LD50 in atropine-treated animals inhibited brain neurotoxic esterase (NTE) and produced mild to moderate ataxia. Considering the extensive use of CPS and its demonstrated potential for causing OPIDN at supralethal doses, additional data are needed to enable quantitative estimates to be made of the neuropathic risk of this compound. Previous work has shown that the ability of OP insecticides to cause acute cholinergic toxicity versus OPIDN can be predicted from their relative tendency to inhibit the intended target, acetylcholinesterase (AChE), versus the putative neuropathic target, NTE, in brain tissue. The present study was designed to clarify the magnitude of neuropathic risk associated with CPS exposures by measuring hen brain AChE and NTE inhibition following dosing in vivo and determining the bimolecular rate constant of inhibition (ki) for each enzyme by the active metabolite, CPS oxon (CPO), in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of hen brain acetylcholinesterase and neurotoxic esterase by chlorpyrifos in vivo and kinetics of inhibition by chlorpyrifos oxon in vitro: application to assessment of neuropathic risk. 768 90

Hens treated with Mipafox (10 mg/kg, sc), sarin (50 micrograms/kg, sc) or parathion (1 mg/kg, sc) daily for 10 days exhibited severe, moderate and no ataxia respectively on 14th day after the start of exposure. The neurotoxic esterase (NTE) activity was significantly inhibited in the brain, spinal cord and platelets of hens treated with mipafox or sarin whereas no change was noticed with parathion treatment. All three compounds significantly inhibited acetylcholinesterase (AChE) activity in the platelets. Spinal cord of hens treated with mipafox, sarin or parathion showed axonal degeneration heavy, moderate and none respectively. It is concluded that repeated administration of equitoxic doses of mipafox, sarin and parathion to hens are marked, moderate and non-delayed neurotoxic respectively.
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PMID:A comparative study of delayed neurotoxicity in hens following repeated administration of organophosphorus compounds. 770 69

A case in which SPECT brain imaging was used in the diagnosis and treatment of chronic effects from acute acetylcholinesterase inhibitor poisoning is presented. The patient was exposed to an insecticide mixture containing phosphorothiate, pyrethrin, piperonyl butoxide, and petroleum distillates, which produced symptoms consistent with acute acetylcholinesterase inhibitor poisoning as well as an upper respiratory tract irritant. Delayed sequelae of gross neurologic symptoms followed, that is, coarse tremor, intermittent hemiballistic movements of the right arm and leg, flaccid muscular tone, fasciculations of muscle groups, muscle cramps, and sensory disturbances. A brain single-photon emission computerized tomography (SPECT) scan was performed 34 mo postexposure, revealing significantly decreased blood flow to the left temporal lobe and to the right and left basal ganglia. The patient's paresthesias were treated with phenytoin, which resulted in worsening of her movement disorder. A trial of amantadine and selegiline (Deprenyl) resulted in a dramatic reduction in dysfunctional movements and ataxia. Post amantadine and selegiline therapy, brain SPECT images revealed significantly improved blood flow with minimally decreased blood flow to the right and left basal ganglia. The use of SPECT scan techniques helped to elucidate objective chronic central nervous system effects subsequent to an acute insecticide exposure and also assisted in the evaluation of the effectiveness of therapeutic intervention.
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PMID:Evaluation of chronic neurological sequelae after acute pesticide exposure using SPECT brain scans. 812 50

Organophosphorus compounds can cause two distinct toxic effects: acute, which are the consequence of acetylcholinesterase (AChE) inhibition and delayed neuropathy being inhibited by inhibition of neuropathy target esterase (NTE) with first signs (ataxia, paralysis) appearing 7-20 days after intoxication. The purpose of this study was to examine interaction of tabun with AChE and NTE and potential neuropathic effects of the compound in vivo. Tabun was more potent inhibitor reacting with more affinity with AChE than NTE of hen brain. The rate of aging of tabun-inhibited AChE was slow (t/2 = 50 hours) while it occurred very rapidly on tabun-inhibited NTE (t/2 = 6.5. min). Experiments in vivo have shown that even a high dose of tabun (12 mg/kg, 120 LD50), given with antidotes, which inhibited 67% of NTE activity did not initiate delayed neuropathic effects. It is concluded that there appears to be no risk for development of delayed neuropathy in tabun poisonings.
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PMID:[Anticholinesterase activity and delayed neurotoxic effects of tabun in hens]. 812 41

Although the immediate action of organophosphorus esters is the inhibition of acetylcholinesterase, some of these compounds also produce a neurodegenerative disorder known as organophosphorus ester-induced delayed neurotoxicity (OPIDN). Tri-o-cresyl phosphate (TOCP) first produced this condition in humans and later in sensitive animal species. OPIDN is characterized by a delay period prior to onset of ataxia and paralysis. The neuropathologic lesions are Wallerian-type degeneration of the axon and myelin in the distal parts of the large tracts in both the central and peripheral nervous systems. In the past decade we have demonstrated that the pathognomonic features of OPIDN are an aberrant increase in autophosphorylation of calcium/calmodulin kinase II (CaM kinase II) and an increase in phosphorylation of cytoskeletal proteins, i.e., MAPs, tubulin, neurofilament triplet proteins, and myelin basic protein. Protein kinase-mediated phosphorylation of cytoskeletal proteins plays a critical role in regulating the growth and maintenance of the axon. We hypothesize that, in OPIDN, hyperphosphorylation of cytoskeletal proteins and axonal swelling are causally linked. Hyperphosphorylation of cytoskeletal proteins decreases their transport rate down the axon relative to their rate of entry into the axon, thus leading to their accumulation. Consistent with this hypothesis is our finding of the anomalous accumulation of phosphorylated neurofilament aggregates in the central and peripheral axons of hens treated with TOCP.
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PMID:The cytoskeleton as a target for organophosphorus ester-induced delayed neurotoxicity (OPIDN). 834 95

We investigated the effects of a turf application of the insecticide diazinon AG500 on Canada geese (Branta canadensis) on a golf course in coastal Washington (USA). On both 19 and 26 March 1987, 1 ha of turf on a golf course located in Birch Bay, Washington was treated with diazinon AG500 at a target application rate of 2.2 kg active ingredient per hectare (AI/ha). Treated areas were then irrigated with 6 mm water. Grass and water samples were collected from three different sites one day before and 1, 3, 7 and 14 days after each application. Diazinon residues > or = 20 ppm were found in golf course grasses for one week after each application. Diazinon residues in study area ponds and creeks were > or = 17 ppb. Samples from two irrigation puddles one day post-application had 1.00 and 0.20 ppm of diazinon, respectively. Numbers of geese present declined following diazinon application; however, no goose mortality was observed. Geese spent 422 and 538 min feeding on the treated areas after the first and second diazinon applications, respectively. One goose feeding in treated areas demonstrated signs of poisoning (lethargy, ataxia) for several hours. Two other geese feeding in the treated areas may have been slightly intoxicated. During carcass searches, three American wigeon (Anas americana) carcasses were found. Based on brain cholinesterase (ChE) levels and gastrointestinal (GI) tract residues of diazinon present, we concluded that these wigeon died from diazinon poisoning. Numerous songbirds (Passeriformes) also fed on the treated turf but no apparent response to the insecticide was observed.
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PMID:Response of Canada geese to a turf application of diazinon AG500. 835 49

Sensitivity of in-life parameters, biochemical endpoints, and susceptibility of various areas of the chicken nervous system to delayed neuropathy induced by tri-orthocresyl phosphate (TOCP) was assessed. Groups of hens were exposed to a single oral dose of TOCP of 0, 50, 200 or 500 mg/kg and the animals observed for 21 days. Perfusion fixed, paraffin embedded tissue sections were stained with Bodian's silver and Luxol blue and semi-thin epoxy sections with toluidine blue. Sciatic and tibial nerves, lumbosacral, midthoracic, and upper cervical spinal cord, medulla oblongata and cerebellum were examined using a semiquantitative scoring system. In pair-dosed hens inhibition of brain and spinal cord neurotoxic esterase (NTE) and cholinesterase and of plasma and erythrocyte cholinesterases was determined 24 hr and 48 hr after administration. At all dose levels NTE in brain and spinal cord and plasma cholinesterase was inhibited markedly. Quantitative inhibition of NTE was seen also in absence of neuropathy. Ataxia and body weight loss occurred in high-dose animals only, while dose-related neuropathy was seen in the distal tibial nerve, medulla oblongata and cerebellum. Ataxia was correlated best with neuropathy in peripheral nerves while degeneration of nerve fibers in the cerebellum, seen best in mid-longitudinal sections, was the most sensitive histological indicator of TOCP-induced delayed neuropathy. The particular susceptibility of spinocerebellar neurons was recognized long ago, but often has been neglected in delayed neurotoxicity studies and respective guidelines. Optimal sensitivity of toxicity tests is a prerequisite for risk assessment, can be cost efficient, and nowadays should be a main interest of animal welfare in order to reduce animals' suffering. Based on these data, determination of NTE inhibition together with histopathological examination of longitudinal sections of distal tibial nerves, mid-longitudinal sections of rostral cerebellum and cross sections of upper cervical spinal cord represents an optimally sensitive and cost efficient test requirement.
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PMID:Susceptibility of various areas of the nervous system of hens to TOCP-induced delayed neuropathy. 908 80

Abou-Donia et al. (in Toxicologist, Vol. 30, 1996) have reported that repeated oral administration of the organo-phosphorus compound triphenyl phosphine (TPPn) to the domestic chicken results in neuropathological changes in the spinal cord and peripheral nerves, accompanied by ataxia and paralysis. This study also noted that single doses of TPPn resulted in no inhibition of the enzymes neuropathy target esterase (NTE) and acetylcholinesterase (AChE). We undertook the present study to determine the biochemical, neuropathological, and clinical effects of single doses of TPPn in the European ferret, a mammalian species shown to be susceptible to organophosphorus-induced neurotoxicity. Eight 12-week-old ferrets were each injected subcutaneously with either 250 mg TPPn/kg bw or 500 mg TPPn/kg bw, or with the peanut oil/ethyl ether vehicle. Twenty-four h after dosing, the brains of 5 animals from each dose group were examined for NTE and AChE activities. The remaining 3 animals in each group were observed for 6 days for the development of clinical signs, after which their brains were processed for the presence of axonal degeneration using the Fink-Heimer silver impregnation method. Single injections of TPPn had no effect on the activities of whole-brain NTE or AChE 24 h after injection. The animals observed for clinical signs showed increasing trunk and hindlimb ataxia beginning 4 days after injection, culminating in fore-and hindlimb paralysis 6 days after injection. All brains exposed to either dose of TPPn showed widespread axonal degeneration extending from the brainstem and cerebellum into midbrain and forebrain areas. The results of this study support the hypothesis that TPPn-induced neurotoxicity is a separate and distinct form of organophosphorus-induced neurotoxicity not dependent on NTE inhibition, and therefore not a variant of organophosphorus-induced delayed neurotoxicity (OPIDN).
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PMID:Organophosphorus-induced neurotoxicity in the absence of neuropathy target esterase inhibition: the effects of triphenyl phosphine in the European ferret. 1036 44


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