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)

OBJECTIVE: To evalute the effects of TAK-147, a novel acetylcholinesterase inhibitor on rat spatial memory deficit using the Morris water maze. METHODS: Morris water maze was used to measure spatial memory in rats, and open field test was used to analysis locomotor activity. RESULTS: Scopolamine (0.4mg/kg,IP) significantly increased the latency period in memory acquisition. Intraperitoneal TAK-147 injection ameliorated scopolamine-induced deficit in a dose-related manner. A significant effect was obtained at doses of 0.3 and 1.0 mg/kg. Both TAK-147 (0.3 and 1.0 mg/kg) and tacrine (3 and 5 mg/kg) significantly reversed scopolamine (1.5 mg/kg) increased latency in memory retrieval. However, TAK-147 had a more potent effect than tacrine. In the locomotor test, TAK-147 created no appreciable change, compared with scopolamine or saline. CONCLUSION: A novel acetycholinesterase inhibitor, TAK-147 ameliorates the scopolamine induced impaired spatial memory in rats.
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PMID:[Effects of TAK-147, a novel acetylcholinesterase inhibitor, on spatial memory deficit as evaluated by Morris water maze of rats] 1253 69

Soman, a powerful inhibitor of acetylcholinesterase, causes an array of toxic effects in the central nervous system including convulsions, learning and memory impairments, and, ultimately, death. We report on the protection afforded by postexposure antidotal treatments, combined with pyridostigmine (0.1 mg/kg) pretreatment, against these consequences associated with soman poisoning. Scopolamine (0.1 mg/kg) or caramiphen (10 mg/kg) were administered 5 min after soman (1.2 LD50), whereas TAB (i.e., TMB4, atropine, and benactyzine, 7.5, 3, and 1 mg/kg, respectively) was injected in rats concomitant with the development of toxic signs. Atropine (4 mg/kg) was given to the two former groups at the onset of toxic symptoms. Caramiphen and TAB completely abolished electrographic seizure activity while scopolamine treatment exhibited only partial protection. Additionally, no significant alteration in the density of peripheral benzodiazepine receptors was noted following caramiphen or TAB administration, while scopolamine application resulted in a complex outcome: a portion of the animals demonstrated no change in the number of these sites whereas the others exhibited markedly higher densities. Cognitive functions (i.e., learning and memory processes) evaluated using the Morris water maze improved considerably by the three treatments when compared to soman-injected animals; the following rank order was observed: caramiphen > TAB > scopolamine. Additionally, statistically significant correlations (r = 0.72, r = 0.73) were demonstrated between two learning parameters and [3H]Ro5-4864 binding to brain membrane. These results show that drugs with a pharmacological profile consisting of anticholinergic and antiglutamatergic properties such as caramiphen and TAB, have a substantial potential as postexposure therapies against intoxication by organophosphates.
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PMID:Anticholinergic and antiglutamatergic agents protect against soman-induced brain damage and cognitive dysfunction. 1283 55

The relationship between cholinesterase (ChE) inhibition and neurobehavioral changes was examined using two ChE-inhibiting organophosphorus (OP) pesticides, fenamiphos and profenofos. Both pesticides produce considerable blood ChE inhibition, but relatively little brain inhibition up to almost lethal doses. Interestingly, pronounced neurobehavioral signs were produced by fenamiphos but not profenofos. After a single oral dose, both pesticides greatly inhibited blood ChE (87-98% inhibition), yet whole brain ChE was only inhibited by 9-14% at the highest doses. Fenamiphos produced dose-dependent effects on many behavioral measures. Despite the similar ChE inhibition profile, profenofos produced no observable changes in behavior. Treatment with anticholinergic drugs was used to evaluate the contribution of peripheral versus central ChE inhibition. Scopolamine (SCO) and methylscopolamine (MSC) were used as central/peripheral and peripheral-only cholinergic receptor blockers, respectively, in combination with fenamiphos. Neither drug altered the effects of fenamiphos on ChE inhibition. Some behavioral effects of fenamiphos were blocked or attenuated only by SCO, whereas other effects were blocked by both drugs. These data indicate that some of the pronounced neurobehavioral changes observed following fenamiphos dosing may be centrally mediated (blocked by SCO only), despite the small amount of inhibition of brain ChE. Other behavioral changes may be mediated more peripherally (blocked by both MSC and SCO). To test the hypothesis that regionally specific ChE inhibition may be responsible for these effects, the same dose of fenamiphos used in the previous studies was given and one half of the brain was dissected into regions. There was significant ChE inhibition in the pons and medulla, cerebellum, striatum, hippocampus, and half-brain but not in the rest-of-brain and frontal cortex; however, the magnitude of inhibition was relatively small across the regions measured. Thus, the centrally mediated neurobehavioral effects of fenamiphos could not be explained based on differential regional brain ChE inhibition alone. Despite the low level of brain ChE inhibition, some behavioral effects of fenamiphos were centrally mediated, and there was little regional specificity of ChE inhibition that could account for the behavioral changes observed.
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PMID:Differential profiles of cholinesterase inhibition and neurobehavioral effects in rats exposed to fenamiphos or profenofos. 1511 2

The present review described the effects of acetylcholinesterase (AChE) inhibition on the cerebral cholinergic neuronal system in the conscious monkey brains with PET. Somatosensory stimulation induced a regional cerebral blood flow (rCBF) response, revealed with [(15)O]H(2)O, in the contralateral somatosensory cortex. Scopolamine resulted in an abolished rCBF response to stimulation, and this abolished rCBF response was recovered by physostigmine, donepezil, and tacrine. Donepezil suppressed AChE activity, analyzed by [(11)C]MP4A, in all cortical regions in a dose-dependent manner. AChE inhibition by donepezil resulted in a dose-dependent increase in acetylcholine levels in the prefrontal cortex as measured by microdialysis. Binding of [(11)C](+)3-PPB to cortical muscarinic receptors was reduced by donepezil, probably in a competitive inhibition manner. Aged monkeys showed less reduction of [(11)C](+)3-PPB binding than young animals. As evaluated by an oculomotor delayed response task, aged monkeys showed impaired working memory performance compared to young monkeys, and the impaired performance was partly improved by the administration of donepezil, due to the facilitation of the cholinergic neuronal system by AChE inhibition by donepezil. These results demonstrated that PET imaging with specifically labeled compounds in combination with microdialysis and a behavioral cognition task could be a useful tool for pre-clinical evaluation of novel drugs.
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PMID:[Pre-clinical evaluation of effects of acetylcholinesterase inhibition on the cerebral cholinergic neuronal system and cognitive function: PET study in conscious monkeys]. 1533 88

Conventional microdialysis methods for measuring acetylcholine (ACh) efflux do not provide sufficient temporal resolution to relate cholinergic transmission to individual stimuli or behavioral responses, or sufficient spatial resolution to investigate heterogeneities in such regulation within a brain region. In an effort to overcome these constraints, we investigated a ceramic-based microelectrode array designed to measure amperometrically rapid changes in extracellular choline as a marker for cholinergic transmission in the frontoparietal cortex of anesthetized rats. These microelectrodes exhibited detection limits of 300 nm for choline and selectivity (> 100 : 1) of choline over interferents such as ascorbic acid. Intracortical pressure ejections of choline (20 mm, 66-400 nL) and ACh (10 and 100 mm, 200 nL) dose-dependently increased choline-related signals that were cleared to background levels within 10 s. ACh, but not choline-induced signals, were significantly attenuated by co-ejection of the acetylcholinesterase inhibitor neostigmine (Neo; 100 mm). Pressure ejections of drugs known to increase cortical ACh efflux, potassium (KCl; 70 mm, 66, 200 nL) and scopolamine (Scop; 10 mm, 200 nL), also markedly increased extracellular choline signals, which again were inhibited by Neo. Scop-induced choline signals were also found to be tetrodotoxin-sensitive. Collectively, these findings suggest that drug-induced increases in current measured with these microelectrode arrays reflect the oxidation of choline that is neuronally derived from the release and subsequent hydrolysis of ACh. Choline signals assessed using enzyme-selective microelectrode arrays may represent a rapid, sensitive and spatially discrete measure of cholinergic transmission.
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PMID:Rapid assessment of in vivo cholinergic transmission by amperometric detection of changes in extracellular choline levels. 1535 21

The aim of these experiments was to assess whether the clinically validated cognition enhancers donepezil (Aricept, E2020) and metrifonate antagonize scopolamine-induced deficits in the cone field, a complex spatial discrimination task. The cone field task allows measurement of the effects of experimental manipulations on working and reference memory (WM and RM), search strategies, and on the speed and latency to execute the task. The effects of a single administration of donepezil (0.1, 0.3, and 1.0 mg kg(-1), p.o.) and metrifonate (30, 60, and 120 mg kg(-1), p.o.) were investigated in adult Harlan-Wistar rats trained to a stable level of performance and pretreated with scopolamine (0.5 mg kg(-1), i.p. 30 min before training). Scopolamine impaired WM without inducing overt non-cognitive side-effects. Donepezil did not antagonize the scopolamine-induced deficits, whereas metrifonate antagonized the WM deficits at the dose of 60 mg kg(-1), but not at 30 or 120 mg kg(-1). Thus, a cholinesterase inhibitor with proven clinical efficacy can antagonize scopolamine-induced spatial memory deficits. The cone field would be a useful component of a behavioral screening battery to test the effects of putative cognition enhancers.
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PMID:Effects of the cholinesterase inhibitors donepezil and metrifonate on scopolamine-induced impairments in the spatial cone field orientation task in rats. 1547 45

Cure of cognitive disorders such as amnesia, attention deficit and Alzheimer's disease is still a nightmare in the field of medicine. Nootropic agents such as piracetam, aniracetam and choline esterase inhibitors like Donepezil are being used to improve memory, mood and behavior, but the resulting side effects associated with these agents have made their use limited. The present study was undertaken to assess the potential of Brahmi rasayana (BR) as a memory enhancer. BR (100 and 200 mg kg(-1) p.o.) was administered for eight successive days to both young and aged mice. Elevated plus maze and passive-avoidance paradigm were employed to evaluate learning and memory parameters. Scopolamine (0.4 mg kg(-1) i.p.) was used to induce amnesia in mice. The effect of BR on whole brain AChE activity was also assessed. Piracetam (200 mg kg(-1) i.p.) was used as a standard nootropic agent. BR significantly improved learning and memory in young mice and reversed the amnesia induced by both scopolamine (0.4 mg kg(-1) i.p.) and natural aging. BR significantly decreased whole brain acetyl cholinesterase activity. BR might prove to be a useful memory restorative agent in the treatment of dementia seen in elderly.
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PMID:Brahmi rasayana improves learning and memory in mice. 1655 Feb 27

Dementia is a mental disorder characterized by loss of intellectual ability sufficiently severe enough to interfere with one's occupational or social activities. Desmodium gangeticum commonly known as Salparni, is widely used in ayurveda for the treatment of neurological disorders. The present work was designed to assess the potential of aqueous extract of D. gangeticum (DG) as a nootropic agent in mice. DG (50, 100 and 200 mg/kg, p.o.) was administered for 7 successive days to both young and older mice. Exteroceptive behavioral models such as elevated plus maze and passive avoidance paradigm were employed to evaluate learning and memory. Scopolamine (0.4 mg/kg, i.p.) induced amnesia and ageing induced amnesia were the interoceptive behavioral models. To delineate the mechanism by which DG exerts nootropic activity, the effect of DG on whole brain AChE activity was also assessed. Piracetam (200 mg/kg, i.p.) was used as a standard nootropic agent. Pretreatment with DG (50, 100 and 200 mg/kg p.o.) for seven successive days significantly improved learning and memory in mice and reversed the amnesia induced by both, scopolamine (0.4 mg/kg, i.p.) and natural ageing. DG also decreased whole brain acetyl cholinesterase activity. Hence, D. gangeticum appears to be a promising candidate for improving memory and it would be worthwhile to explore the potential of this plant in the management of dementia and Alzheimer disease.
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PMID:Antiamnesic effects of Desmodium gangeticum in mice. 1694 93

The fact that muscarinic antagonists may evoke a psychotic state ('antimuscarinic psychosis'), along with findings of cholinergic alterations in schizophrenia, have kindled an interest in the involvement of the cholinergic system in this disorder. Latent inhibition (LI) is a cross-species phenomenon manifested as a poorer conditioning of a stimulus seen when the stage of conditioning is preceded by a stage of repeated nonreinforced pre-exposure to that stimulus, and is considered to index the capacity to ignore irrelevant stimuli. Amphetamine-induced LI disruption and its reversal by antipsychotic drugs (APDs) is a well-established model of positive symptoms of schizophrenia. Here, we tested whether the muscarinic antagonist scopolamine would disrupt LI and whether such disruption would be reversed by APDs and by the acetylcholinesterase inhibitor physostigmine. The results showed that scopolamine at doses of 0.15 and 0.5 mg/kg disrupted LI, and that this effect was due to the action of the drug in the pre-exposure stage, suggesting a role of muscarinic transmission in attentional processes underlying LI. Both the typical and the atypical APDs, haloperidol and clozapine, reversed scopolamine-induced LI disruption when given in conditioning or in both stages, but not in pre-exposure, indicating that the mechanism of antipsychotic action in this model is independent of the mechanism of action of the propsychotic drug. Scopolamine-induced LI disruption was reversed by physostigmine (0.05 and 0.15 mg/kg), which was ineffective in reversing amphetamine-induced LI disruption, pointing to distinct mechanisms underlying LI disruption by these two propsychotic drugs. The latter was further supported by the finding that unlike amphetamine, the LI-disrupting doses of scopolamine did not affect activity levels. We propose scopolamine-induced LI disruption as a model of cholinergic-related positive symptoms in schizophrenia.
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PMID:Scopolamine induces disruption of latent inhibition which is prevented by antipsychotic drugs and an acetylcholinesterase inhibitor. 1697 98

Behavioral, electroencephalographic (EEG) and neuropathological effects of methomyl, a carbamate insecticide reversibly inhibiting acetylcholinesterase activity, were studied in naive or lithium chloride (24 h, 3 mEq/kg, s.c.) pretreated male Wistar rats. In naive animals, methomyl with equal potency produced motor limbic seizures and fatal status epilepticus. Thus, the CD50 values (50% convulsant dose) for these seizure endpoints were almost equal to the LD50 (50% lethal dose) of methomyl (13 mg/kg). Lithium pretreated rats were much more susceptible to convulsant, but not lethal effect of methomyl. CD50 values of methomyl for motor limbic seizures and status epilepticus were reduced by lithium pretreatment to 3.7 mg/kg (a 3.5-fold decrease) and 5.2 mg/kg (a 2.5-fold decrease), respectively. In contrast, lithium pretreatment resulted in only 1.3-fold decrease of LD50 value of methomyl (9.9 mg/kg). Moreover, lithium-methomyl treated animals developed a long-lasting status epilepticus, which was not associated with imminent lethality observed in methomyl-only treated rats. Scopolamine (10 mg/kg) or diazepam (10 mg/kg) protected all lithium-methomyl treated rats from convulsions and lethality. Cortical and hippocampal EEG recordings revealed typical epileptic discharges that were consistent with behavioral seizures observed in lithium-methomyl treated rats. In addition, convulsions induced by lithium-methomyl treatment were associated with widespread neurodegeneration of limbic structures. Our observations indicate that lithium pretreatment results in separation between convulsant and lethal effects of methomyl in rats. As such, seizures induced by lithium-methomyl administration may be an alternative to lithium-pilocarpine model of status epilepticus, which is associated with high lethality.
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PMID:Lithium-methomyl induced seizures in rats: a new model of status epilepticus? 1709 27


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