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)

Several reports have suggested that exposure to organophosphate pesticides damages the visual system. The prolonged effects of an acute dose of fenthion (dimethyl 3-methyl-4-methylthiophenyl phosphorothionate) were studied on the cholinergic system of the rat retina. Fenthion was administered in a single dose of 0 or 100 mg/kg (sc, in corn oil) to adult, male, Long-Evans rats. The animals were killed 4, 14, or 56 days after treatment and cholinesterase (ChE) activity as well as muscarinic receptor (mChR) function measured in the retina and frontal cortex. Fenthion produced 89% inhibition of ChE activity in both tissues at 4 days, and, although there was recovery, slight (15%) inhibition of the enzyme activity was still observed at 56 days in both tissues. A long-lasting decrease in carbachol-stimulated inositolphosphate (IP) release was observed following fenthion treatment in the retina: IP release was depressed at 4 days and this depression persisted up to 56 days after dosing. The density of mChR in the retina as well as in the cortex was decreased by 14-20% at 4 days and returned to control levels by 56 days. Fenthion had no effect on the metabolism of phospholipids in the retina following intraocular injections of labeled precursors [3H]myo-inositol, [methyl-14C]choline, or [2-3H]glycerol 4 days after fenthion treatment. These prolonged effects of fenthion on mChR function (signal transduction) appear to be specific to the retina as the cortex showed no change in receptor-stimulated IP release even in the presence of significant mChR down-regulation and ChE inhibition. This dose of fenthion did not produce overt morphological changes in the retina or in the cortex, as observed with light microscopy, although an increase in glial fibrillary acidic protein immunoreactivity (GFAP IR) extending from the internal limiting membrane to the external limiting membrane of the retina was noted. This increase in GFAP IR was observed at 14 days and persisted as long as 56 days post-treatment in the retina, but was not noted in the cortex at any of the time points studied. Thus, this long-lasting perturbation in the retinal cholinergic second messenger system induced by fenthion may occur independently of depressed ChE activity and down-regulation of mChR.
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PMID:Fenthion produces a persistent decrease in muscarinic receptor function in the adult rat retina. 817 35

These experiments examined the relationship between behavioral alterations and neurochemical changes in rats exposed repeatedly to disulfoton, an organophosphate cholinesterase inhibitor. Male Long-Evans rats were injected ip for 30 days with 0, 0.5, 1, or 2 mg/kg of disulfoton in corn oil. Clinical signs and motor activity were measured during the course of repeated exposure. Cognitive function, as measured in the Morris water maze, and passive avoidance procedures were assessed near the end of the dosing regimen. Regional brain acetylcholinesterase (AChE) activity was measured during the course of dosing while the total number of muscarinic receptors was measured at the end of the dosing regimen. Tolerance developed rapidly to the clinical signs produced by disulfoton, but not to the disulfoton-induced decrease in motor activity. Disulfoton affected the acquisition of water maze performance, but had no effect on passive avoidance acquisition or retention. Repeated exposure to disulfoton decreased brain AChE activity and the number of [3H]quinuclidinyl benzilate binding sites. These data indicate that, in spite of muscarinic receptor down-regulation that followed repeated exposure to disulfoton, animals become tolerant to only some of the functional effects produced by this chemical.
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PMID:Characterization of disulfoton-induced behavioral and neurochemical effects following repeated exposure. 844 87

The purpose of this study was to assess intraspecies differences in behavioral and autonomic function in three strains of rat following administration of diisopropyl fluorophosphate (DFP), an irreversible inhibitor of acetylcholinesterase activity. Male rats of the Long-Evans (LE), Fischer 344 (F344), and Sprague-Dawley (SD) strains wer administered DFP at doses of 0-1.5 mg/kg (sc). The animals were placed 60 min later into one of two motor activity chambers and tested for 30 min. Motor activity was measured using either a Doppler-based system or a commercial photocell device. Following measurement of motor activity in the Doppler system, body temperature (Tb) was measured and blood was then withdrawn by cardiac puncture and analyzed for serum cholinesterase activity (ChE). The remaining rats were retested 1 d after DFP administration in the photocell device. The results showed a significant influence of strain on the effects of DFP. Motor activity of LE rats was reduced by DFP at doses of 1.0 and 1.5 mg/kg, whereas the activity of F344 rats was reduced only at 1.5 mg/kg. The relative sensitivity of SD rats depended on the device used to measure motor activity. The SD rats resembled F344 rats in their response to DFP when motor activity was measured in the photocell device, and LE rats when motor activity was measured in the Doppler system. The Tb of F344 rats was unaffected by DFP, while the LE and SD rats became hypothermic at 1.5 mg/kg. The DFP-induced inhibition of serum ChE activity was significantly less in F344 rats. All three strains retested the day after DFP still showed significant decreases in motor activity. Overall, it appears that the F344 strain is relatively resistant to the behavioral and autonomic effects of DFP. This intraspecies variability should be considered in selecting appropriate experimental models for assessing the neurotoxicological hazards of cholinesterase-inhibiting pesticides.
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PMID:Strain comparisons of DFP neurotoxicity in rats. 845 May 57

Risk assessment of the neurotoxicology of organophosphate (OP) pesticides calls for a thorough understanding of the relationship between tissue cholinesterase (ChE) activity and changes in behavioral and autonomic responses to OP treatment. To address this issue, motor activity, core and skin temperature, and serum ChE activity were measured 2 h after rats of the Long-Evans strain were treated with the OP, diisopropyl fluorophosphate (DFP) at a dose of 0, 0.1, 0.25, 0.5, 0.75, 1.0, 1.25, and 1.5 mg/kg (SC). DFP doses > or = 0.25 mg/kg led to significant decreases in serum ChE activity, whereas doses of > or = 0.5 mg/kg caused reductions in motor activity and body temperature. The highest dose of DFP caused an increase in tail skin temperature, indicating an elevation in skin blood flow. A hockey stick regression analysis was used to determine threshold inhibition in ChE activity associated with depressions in motor activity and colonic temperature. The threshold serum ChE activity, relative to controls for inhibition of motor activity and reduction in body temperature was 46%. A wide range in individual motor activity and colonic temperature responses was noted when the inhibition in ChE activity exceeded threshold levels. This may be indicative of marked genetic variability to ChE inhibition. That is, rats appear to be either responsive or unresponsive when subjected to extreme inhibition in ChE activity. This pattern has been reported in other rodents and may represent a fundamental aspect of ChE toxicity.
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PMID:Relationship between serum cholinesterase activity and the change in body temperature and motor activity in the rat: a dose-response study of diisopropyl fluorophosphate. 845 84

Acute exposure to diisopropyl fluorophosphate (DFP) causes irreversible inhibition of acetylcholinesterase activity, leading to various behavioral and autonomic sequelae including hypothermia, reduced motor activity, and other neurological dysfunctions. To characterize the acute response and recovery of autonomic and behavioral processes to DFP exposure, rats of the Long-Evans strain were implanted with radiotransmitters that allowed the monitoring of core temperature, heart rate, and motor activity in unrestrained animals 24 h/d. These parameters were monitored for 96 h following subcutaneous injection of DFP at a dose of 0, 0.1, or 1.0 mg/kg. Rats given 0 and 0.1 mg/kg DFP displayed an increase in core temperature and motor activity during the first 24 h postinjection. The 1.0 mg/kg group showed a typical hypothermic response for the first 24 h following DFP administration. Core temperature decreased a maximum of 1.9 degrees C by 5 h after DFP and then started to recover, reaching control levels by 17 h after DFP treatment. Motor activity was also depressed during the first 24-h period in the 1.0 mg/kg group. Heart rate was initially elevated above basal levels in all treatment groups for several hours after treatment, but the 1.0 mg/kg group showed a decrease in heart rate at the time when core temperature began its recovery from hypothermia. Core temperature was the only parameter significantly affected by DFP during the 24-96 h recovery phase. The 0.1 and 1.0 mg/kg groups showed a significant elevation in core temperature for the 3 d after DFP administration. The elevation in core temperature during the recovery from DFP treatment may represent an important facet of the acute cholinergic neurotoxicity of organophosphate compounds.
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PMID:Acute and delayed effects of diisopropyl fluorophosphate on body temperature, heart rate, and motor activity in the awake, unrestrained rat. 850 68

Long Evans rats were treated for 90 days with water-soluble, insoluble or chelated aluminium compounds. The daily treatments given were as follows: controls, NaCl (100 mg/kg body weight) plus citric acid (30 mg/kg); AlCl3 (30 or 100 mg/kg); Al(OH)3 (100 mg/kg) plus citric acid (30 mg/kg); Al(OH)3 (300 mg/kg). Their learning ability was determined in the labyrinth test at day 90, and the choline-acetyltransferase, acetylcholinesterase activity and aluminium content of the brains were measured. Soluble and chelated aluminium compounds seriously worsened the learning ability, and the aluminium content of the brain was elevated. Acetylcholinesterase activity increased and choline-acetyltransferase activity decreased, resulting in a diminished cholinergic activity, which is a characteristic of Alzheimer's disease.
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PMID:Neurotoxic effect of enteral aluminium. 850 21

In view of numerous studies demonstrating that intracerebral implants of fetal neural tissue can promote functional recovery and structural repair in the damaged brain, the present study examined the potential use of neocortical transplantation in newborn rats that sustained hypoxic-ischemic brain injury. Ischemic insult was induced in Long-Evans, black-hooded 1-week-old rats by unilateral common carotid artery occlusion followed by 2.5 h of hypoxia in 8% O2. One week later, animals received neocortical block transplants. At 2-6 weeks posttransplantation, animals were sacrificed and their brains examined histologically. Transplants survived in over 80% of the animals and the presence of acetylcholinesterase-positive fibers crossing the host-transplant interface provided evidence of transplant integration with the host brain. However, morphometric measurements revealed that the transplants were unable to reduce the hypoxia-ischemia-induced degeneration in the host hippocampus, caudate-putamen, or thalamus. Nonetheless the demonstrated survival of grafts in the neonatal hypoxia-ischemia model suggests a potential therapeutic effect.
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PMID:Use of fetal cortical grafts in hypoxic-ischemic brain injury in neonatal rats. 856 4

Adult Long-Evans female rats sustained electrolytic fimbria-fornix lesions and, two weeks later, received intrahippocampal suspension grafts of fetal septal tissue. Sham-operated and lesion-only rats served as controls. Between 6.5 and 8 months after grafting, both the [3H]choline accumulation and the electrically evoked [3H]acetylcholine ([3H]ACh) release were assessed in hippocampal slices. The release of [3H]ACh was measured in presence of atropine (muscarinic antagonist, 1 microM), physostigmine (acetylcholinesterase inhibitor, 0.1 microM), oxotremorine (muscarinic agonist, 0.01 microM-10 microM), mecamylamine (nicotinic antagonist, 10 microM), methiothepin (mixed 5-HT1/5-HT2 antagonist, 10 microM), 8-OH-DPAT (5-HT1A agonist, 1 microM), 2-methyl-serotonin (5-HT3 agonist, 1 microM) and CP 93129 (5-HT1B agonist, 0.1 microM-100 microM), or without any drug application as a control. In lesion-only rats, the specific accumulation of [3H]choline was reduced to 46% of normal and the release of [3H]ACh to 32% (nCi) and 43% (% of tissue tritium content). In the grafted rats, these parameters were significantly increased to 63%, 98% and 116% of control, respectively. Physostigmine reduced the evoked [3H]ACh release and was significantly more effective in grafted (-70%) than in sham-operated (-56%) or lesion-only (-54%) rats. When physostigmine was superfused throughout, mecamylamine had no effect. Conversely, atropine induced a significant increase of [3H]ACh release in all groups, but this increase was significantly larger in sham-operated rats (+209%) than in the other groups (lesioned: +80%; grafted: +117%). Oxotremorine dose-dependently decreased the [3H]ACh release, but in lesion-only rats, this effect was significantly lower than in sham-operated rats. Whatever group was considered, 8-OH-DPAT, methiothepin and 2-methyl-serotonin failed to induce any significant effect on [3H]ACh release. In contrast, CP 93129 dose-dependently decreased [3H]ACh release. This effect was significantly weaker in grafted rats than in the rats of the two other groups. Our data confirm that cholinergic terminals in the intact hippocampus possess inhibitory muscarinic autoreceptors and serotonin heteroreceptors of the 5-HT1B subtype. They also show that both types of receptors are still operative in the cholinergic terminals which survived the lesions and in the grafted cholinergic neurons. However, the muscarinic receptors in both lesioned and grafted rats, as well as the 5-HT1B receptors in grafted rats show a sensitivity which seems to be downregulated in comparison to that found in sham-operated rats. In the grafted rats, both types of downregulations might contribute to (or reflect) an increased cholinergic function that results from a reduction of the inhibitory tonus which ACh and serotonin exert at the level of the cholinergic terminal.
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PMID:Downregulation of muscarinic- and 5-HT1B-mediated modulation of [3H]acetylcholine release in hippocampal slices of rats with fimbria-fornix lesions and intrahippocampal grafts of septal origin. 878 10

Recent reports indicate that organophosphate insecticides, in addition to inhibiting acetylcholinesterase activity, can bind directly at a subset of muscarinic receptors, which also bind cis-methyldioxolane with high affinity. Muscarinic receptors are known to act through at least two second messenger systems, either the stimulation of phosphoinositide turnover (mediated through the M1 and M3 receptor subtypes) or the inhibition of cAMP formation (mediated through the M2 and M4 receptor subtypes). We have investigated the action of the active forms of parathion, malathion, and chlorpyrifos (paraoxon, malaoxon, and chlorpyrifos oxon, respectively) on these second messenger systems in cortical slices from adult male Long-Evans rats. Paraoxon, malaoxon, and chlorpyrifos oxon (10(-8) to 10(-4) M) inhibited forskolin-stimulated cAMP formation in a concentration-dependent manner. The effect on cAMP formation was blocked by the muscarinic antagonist atropine (10 microM). These results suggest that paraoxon, malaoxon, and chlorpyrifos oxon can act as agonists at the M2 and/or M4 subset of muscarinic receptors. In addition, chlorpyrifos may have another site of action. In contrast, none of the organophosphates had any effect on basal or carbachol-stimulated phosphoinositide hydrolysis. The differential activity on these two second messenger systems make it unlikely that the observed effects on cAMP formation are due to increases in endogenous acetylcholine resulting from inhibition of acetylcholinesterase.
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PMID:Organophosphorus compounds preferentially affect second messenger systems coupled to M2/M4 receptors in rat frontal cortex. 884 8

Chlorpyrifos (CHL) is a commonly used organophosphate (OP) pesticide which irreversibly inhibits acetylcholinesterase activity in the CNS. Little is known regarding the thermoregulatory effects of CHL when administered orally and whether the sensitivity to CHL is affected by sex. To address these issues, male and female rats of the Long-Evans strain were administered 0, 10, 50, or 80 mg/kg CHL by gavage while core temperature (T(c)) and motor activity (MA) were monitored continuously by telemetry. Females were generally more sensitive than males to CHL. Significant hypothermic responses to CHL were observed in males administered 80 mg/kg and in females administered 10-80 mg/kg. Following recovery from hypothermia T(c) of both males and females underwent a significant elevation during the light phase 1-2 days after CHL exposure. CHL-induced hyperthermia was blocked in male and female rats by administration of 200 mg/kg sodium salicylate (SS), an antipyretic agent. Male castrated rats were markedly more sensitive to the hypothermic and hyperthermic effects of CHL compared to sham operated controls. On the other hand, ovariectomized female rats responded to CHL in a similar fashion as the sham operated controls. Thus, testicular function may be important in determining greater resistance to CHL in male rats. It appears that exposure to CHL leads to a delayed fever which involves activation of CNS pathways normally involved in fever. This mechanism could be responsible for the febrile response to OP pesticides commonly observed in humans exposed to OPs.
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PMID:Hypothermia and delayed fever in the male and female rat exposed to chlorpyrifos. 912 69


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