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)

Previous studies have shown that basal forebrain lesions using different excitotoxins produce similar decreases in cortical choline acetyltransferase, but differential effects on memory. However, basal forebrain cholinergic neurons send efferents to the amygdala and cortex. The present studies compared the effects of several excitotoxins on choline acetyltransferase levels in both of these structures. Lesions of the basal forebrain were made in rats by infusing different doses of either alpha-amine-3-hydroxy-5-methyl-4-isoxazole propionic acid, ibotenic acid, quisqualic acid, quinolinic acid or N-methyl-D-aspartic acid and measuring choline acetyltransferase seven days later. All of the excitotoxins exerted a differential response on cholinergic neurons of the basal forebrain projecting to the cortex or amygdala. Quinolinic acid was a more potent neurotoxin to cholinergic neurons innervating the amygdala than those projecting to the cortex. In contrast, quisqualic acid and alpha-amine-3-hydroxy-5-methyl-4-isoxazole were more potent neurotoxins to the cortical projection. alpha-Amine-3-hydroxy-5-methyl-4-isoxazole propionic acid was the most potent excitotoxin for destroying cholinergic neurons innervating either the cortex or amygdala. A parallel neurotoxic response was obtained in the cortex and amygdala following infusion of ibotenic acid or N-methyl-D-aspartic acid with little selectivity for choline acetyltransferase depletion in the cortex or amygdala. Histological analysis of the injection site revealed that acetylcholinesterase-positive neurons were destroyed by the excitotoxins in a dose-dependent manner. Excitotoxins (ibotenic acid, quinolinic acid, N-methyl-D-aspartic acid) that produce the greatest impairments in memory were found to produce the greatest depletion of choline acetyltransferase in the amygdala.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Excitotoxic lesions of rat basal forebrain: differential effects on choline acetyltransferase in the cortex and amygdala. 128 23

The aim of the present study was to clarify the role of the basal forebrain (BF)-cortical cholinergic system in visual attentional function by investigating the effect of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-induced lesions of the basal forebrain on performance of a five-choice serial reaction time task. AMPA lesions in the present study produced a profound effect on performance of the task, as measured by choice accuracy and correct response latency. This deficit was significantly greater than that observed in earlier studies following ibotenate- or quisqualate-induced lesions of the BF. However, detailed histological and biochemical analysis revealed three rather different BF lesions depending upon the batch of AMPA supplied. In one group of animals (BF/1) the deficits in task performance were substantially greater and longer lasting compared to another group of lesioned animals (BF/2), which showed behavioral recovery several months following the lesion. The former sustained severe pallidal damage in addition to marked reductions in cortical ChAT activity. Support for the attentional nature of these deficits was obtained by the ability to improve task performance in BF/1 lesioned animals by increasing the duration of the visual stimulus and thus reducing the attentional load placed on these animals. In contrast, performance deficits could be reinstated in those animals showing behavioral recovery (BF/2) by reducing the duration of the visual stimulus and thus increasing attentional load. In the second experiment more discrete lesions of the magnocellular cholinergic neurons were made, resulting in extensive reduction of cortical ChAT activity with considerably less neuronal loss from the dorsal pallidum compared to the BF/1 lesion group. Once again, deficits on the task were substantially greater than observed previously following either quisqualate- or ibotenate-induced BF lesions. Furthermore, the cholinergic specificity of these deficits was supported by the attenuation of behavioral impairments following administration of the anti-cholinesterase physostigmine. Taken together with our earlier work, which has failed to demonstrate mnemonic deficits following lesions to the magnocellular neurons of the nucleus basalis of Meynert, these results suggest that the most consistent deficit produced following lesions of the BF-cortical cholinergic system is attentional dysfunction Analogous deficits in visual attention are also seen in patients with Alzheimer's disease, which can also be improved by anti-cholinesterase treatment.
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PMID:AMPA-induced excitotoxic lesions of the basal forebrain: a significant role for the cortical cholinergic system in attentional function. 751 37

A series of N-benzylpiperidines (2a-d, 10) with novel isoxazole-containing tricycles has been prepared. This series has shown potent in vitro inhibition of the enzyme acetylcholinesterase (AChE), with IC50S = 0.33 - 3.6 nM. Compound 2a was the most potent inhibitor with an IC50 = 0.33 +/- 0.09 nM. Derivatives 2a-d and 10 displayed weak in vitro inhibition of butyrylcholinesterase (BuChE) with IC50S = 600 - 23,000 nM. The most selective compound was 2a with a BuChE/AChE ratio in excess of 4 orders of magnitude (> 10,000). Pyrrolobenzisoxazole 2a also displayed a favorable profile in vivo. In microdialysis experiments, 2a produced a 200% increase in extracellular levels of acetylcholine (ACh) at a dose of 0.4 mg/kg in freely moving, conscious rats. Peripheral side effects (salivation ED50 = 26 +/- 1.5 mg/kg) and acute lethality (LD50[1 h] = 42 mg/kg) were observed at > 60-fold higher doses. These data indicate that 2a is an AChE inhibitor with good central selectivity and a favorable margin of safety. Compound 2a, designated as CP-118,954, is currently in clinical development for the treatment of cognitive disorders.
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PMID:5,7-dihydro-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-6H- pyrrolo[3,2-f]-1,2-benzisoxazol-6-one: a potent and centrally-selective inhibitor of acetylcholinesterase with an improved margin of safety. 763 41

The present study was undertaken to study the effect of reduced cortical cholinergic activity on gamma-aminobutyric acid (GABA)ergic and glutamatergic mechanisms in cholinoceptive cortical target regions which are assumed to play an important role for realizing cognitive functions. The densities of cortical muscarinic cholinergic receptor subtypes and corresponding receptor genes m1 through m4, N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) and kainate glutamate receptor subtypes as well as GABAA and benzodiazepine receptors were measured in rats 1 week after unilateral ibotenic acid lesion of the nucleus basalis magnocellularis (Nbm) applying quantitative receptor autoradiography and in situ hybridization. Ibotenic acid lesion resulted in a striking loss of acetylcholinesterase (AChE) staining in the lesioned Nbm which is associated with a 60% decrease in AChE staining and a 30% reduction in [3H]hemicholinium-3 binding in frontal and parietal cortical regions as well fore- and hindlimb areas ipsilateral to the lesion, being more prominent in the more rostral cortical regions. M1-muscarinic cholinergic receptor binding was not changed in any of the cortical regions studied 1 week after lesion. M2-muscarinic receptor binding levels are slightly increased in the parietal cortex only. The lesion-induced increase in parietal cortical M2-muscarinic receptor binding is complemented by an increase in the hybridization signal for the corresponding m4-mRNA transcript. In cortical regions displaying a reduced activity of AChE and decreased levels of high-affinity choline uptake sites due to forebrain cholinergic lesion, NMDA receptor binding was markedly reduced in comparison to the unlesioned brain side whereas AMPA and kainate binding has been significantly increased in these regions. Muscimol binding to GABAA receptors was increased in the rostral portions of frontal and parietal cortices as compared with the unlesioned brain side. Binding levels of benzodiazepine receptors were not affected by the lesion in any of the cortical regions studied. The differential changes in glutamate and GABA receptor subtypes following lesion might be regarded as the consequence of a cortical reorganization compensating for the reduced cholinergic presynaptic input. The data further suggest that presynaptic cortical cholinergic deficits might affect both glutamatergic and GABAergic functions with different intensity and different directions.
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PMID:Ibotenic acid lesion of nucleus basalis magnocellularis differentially affects cholinergic, glutamatergic and GABAergic markers in cortical rat brain regions. 770 21

Unilateral lesions of the nucleus basalis magnocellularis (NBM) produced by alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid in rats caused, 8-10 weeks after the lesion, a 94% reduction in cortical acetylcholinesterase fibres and reduced activities of acetylcholinesterase and choline acetyltransferase by 70-80% in the frontal cortex ipsilateral to the lesion. In anaesthetized unlesioned control rats, iontophoretic administration of acetylcholine and carbachol produced atropine-sensitive inhibition and excitation of frontal cortical neurones, effects similar to those produced by electrically stimulating the NBM. The lesion reduced cortical neuronal firing rates but increased the percentage and sensitivity of neurones responding to acetylcholine, the predominant response changing from inhibition to excitation; response duration increased but latency was unaffected. The size of the response of individual neurones to carbachol, but not the percentage of sensitive neurones, was also increased in lesioned animals. The proportion of neurones responding to bicuculline and their individual sensitivities were increased by the lesion, suggesting that the lesion increased GABAergic tone; responses to glutamate were unchanged. The lesion did not affect the proportion of neurones in which acetylcholine modulated neuronal responses but reversed the nature of the modulation to predominantly excitatory; excitation was the predominant response to electrical forepaw stimulation in unlesioned control animals. This suggests a possible interaction between GABAergic and cholinergic mechanisms in selective attention and processing of cognitive information. Acute administration of di-isopropyl fluorophosphate to unlesioned animals significantly increased the number of frontal cortical neurones responding to acetylcholine, without affecting individual neuronal sensitivity or responses to carbachol and glutamate. The similarity of these effects to those of acetylcholine in lesioned animals suggests that the increased sensitivity to acetylcholine in the latter was due to loss of acetylcholinesterase, enabling diffusion of acetylcholine to more distant neurones. However, acetylcholinesterase does not hydrolyse carbachol and therefore it is necessary to postulate a different post-synaptic mechanism to explain the lesion-induced increases in the sensitivities of individual neurones to carbachol and to acetylcholine; interpretation of experimental findings should take these two mechanisms into account.
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PMID:An iontophoretic study of the effects of alpha-amino-hydroxy-5-methyl-4-isoxazole propionic acid lesions of the nucleus basalis magnocellularis on cholinergic and GABAergic influences on frontal cortex neurones of rats. 791 93

Unilateral S-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) lesions of the nucleus basalis magnocellularis (nbm), which produced persistent and extensive ChAT-positive cell loss within the nbm and depletion of cortical cholinergic markers in the frontal cortex, increased both the number and sensitivity of individual frontal cortical neurones responding to iontophoretic administration of ACh. The lesion also increased the sensitivity of individual neurones to carbachol but the increase in the number of neurones responding to carbachol was transient and had returned to normal 4 weeks after lesion. The sensitivity of individual neurones to glutamate was unchanged by the lesion. The percentage of cortical neurones responding to ACh, but not the sensitivity of individual neurones was restored to the prelesion level, 6-8 weeks after cholinergic transplants to the lesioned frontal cortex; cholinergic transplants to the more distant parietal cortex were only effective after 6 months whereas noncholinergic transplants were ineffective at both time intervals. Cholinergic transplants placed in the frontal cortex 6-8 weeks or 6 months before nbm lesion offered some protection from the effects of the lesion, particularly at 6 months but were ineffective when placed into the parietal cortex. Lesion of the nbm also reduced basal firing rate of spontaneously active neurones and this was not restored by any of the transplants. The results are discussed in the light of quantitative measurements of acetylcholinesterase-positive fibre outgrowth from the transplant into the recording area, which are described in the preceding manuscript [20].
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PMID:Changes in the sensitivity of frontal cortical neurones to acetylcholine after unilateral lesion of the nucleus basalis with alpha-amino-3-OH-4-isoxozole propionic acid (AMPA): effects of basal forebrain transplants into neocortex. 899 27

Huperzine A (HUP) is a potent reversible inhibitor of acetylcholinesterase (AChE) that crosses the blood-brain barrier. Its ability to prevent seizures and subsequent hippocampal neuropathological changes induced by the organophosphate soman was studied in guinea pigs. Results were compared to guinea pigs treated with pyridostigmine (PYR, 0.2 mg/kg, subcutaneously). HUP pretreatment at 0.5 mg/kg, intraperitoneally, totally prevented seizures and ensured the survival of all animals for 24 h after intoxication. Hippocampal tissue was then free of any neuronal damage. Comparatively, all animals pretreated with PYR exhibited epileptic activity after soman poisoning and five of six animals died. Examination of the hippocampus of the only surviving guinea pig pretreated with PYR showed extensive neuropathological changes. Although HUP or PYR induced similar inhibitions of blood AChE activity, only HUP pretreatment led to a decrease in central AChE activity. In binding studies on guinea-pig brain homogenates, HUP had no affinity for muscarinic, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and gamma-aminobutyric acid (GABA)A receptors and only a very low one for N-methyl-D-aspartate (NMDA) receptors. In conclusion, HUP, unlike PYR, protects against soman-induced convulsions and neuropathological changes in the hippocampus. This efficacy seems to be related to a protection by HUP of both peripheral and central stores of AChE.
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PMID:Efficacy of huperzine in preventing soman-induced seizures, neuropathological changes and lethality. 934 91

Huperzine A, a nootropic alkaloid isolated from a Chinese herb, has been proposed as one of the most promising agents to treat Alzheimer's disease. Recently, the agent was found to inhibit the N-methyl-D-aspartate (NMDA) receptors in rat cerebral cortex in addition to causing an inhibitory effect on acetylcholinesterase. In the present study, the mechanisms underlying NMDA receptor inhibition were investigated using whole-cell voltage-clamp recording in CA1 pyramidal neurons acutely dissociated from rat hippocampus. Huperzine A reversibly inhibited the NMDA-induced current (IC(50)=126 microM, Hill coefficient=0.92), whereas it had no effect on the current induced by alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate or kainate. The effect was non-competitive, and showed neither 'voltage-dependency', nor 'use-dependency'. The IC(50) values of huperzine A were neither altered by changing the concentrations of glycine (2-0.2 microM) and pH (7.4-6.7) in the external solution, nor by addition of Zn(2+) (5 microM) and dithiothreitol (5 mM) to the external solution. However, addition of spermine (200 microM) to the external solution caused a parallel shift to the right of the huperzine A concentration-response curve. From these we suggest that huperzine A acts as a non-competitive antagonist of the NMDA receptors, via a competitive interaction with one of the polyamine binding sites. The potential relevance of NMDA receptor antagonist activity of huperzine A to the treatment of Alzheimer's disease is discussed.
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PMID:Huperzine A, a nootropic alkaloid, inhibits N-methyl-D-aspartate-induced current in rat dissociated hippocampal neurons. 1151 31

Acetylcholine (Ach) has been considered a major neurotransmitter in the inner ear efferent nerve endings. A bioassay analysis has shown that the electrical stimulation of the crossed olivocochlear bundle increased the Ach-like activity in the perilymph. Applying in vivo microdialysis techniques and high-performance liquid chromatography to the perilymph, the change of Ach level was thus measured before and after alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), a glutamate receptor agonist, was added to the perfusate. Ach was only detectable when the perfusate contained an acetylcholinesterase inhibitor. The level of Ach increased 2-3-fold immediately after AMPA was administered. Our data suggest that the afferent stimulation, such as the administration of AMPA, may therefore induce the release of Ach from the efferent nerve endings.
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PMID:The glutamate receptor agonist, AMPA, induces acetylcholine release in guinea pig cochlea; a microdialysis study. 1157 30

The pathophysiology of Alzheimer's disease is complex and involves several different biochemical pathways. These include defective beta-amyloid (Abeta) protein metabolism, abnormalities of glutamatergic, adrenergic, serotonergic and dopaminergic neurotransmission, and the potential involvement of inflammatory, oxidative and hormonal pathways. Consequently, these pathways are all potential targets for Alzheimer's disease treatment and prevention strategies. Currently, the mainstay treatments for Alzheimer's disease are the cholinesterase inhibitors, which increase the availability of acetylcholine at cholinergic synapses. Since the cholinesterase inhibitors confer only modest benefits, additional non-cholinergic Alzheimer's disease therapies are urgently needed. Several non-cholinergic agents are currently under development for the treatment and/or prevention of Alzheimer's disease. These include anti-amyloid strategies (e.g. immunisation, aggregation inhibitors, secretase inhibitors), transition metal chelators (e.g. clioquinol), growth factors, hormones (e.g. estradiol), herbs (e.g. Ginkgo biloba), nonsteroidal anti-inflammatory drugs (NSAIDs, e.g. indomethacin), antioxidants, lipid-lowering agents, antihypertensives, selective phosphodiesterase inhibitors, vitamins (E, B12, B6, folic acid) and agents that target neurotransmitter or neuropeptide alterations. Neurotransmitter receptor-based approaches include agents that modulate certain receptors (e.g. nicotinic, muscarinic, alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid [AMPA], gamma-aminobutyric acid [GABA], N-methyl-D-aspartate [NMDA]) and agents that increase the availability of neurotransmitters (e.g. noradrenergic reuptake inhibitors). Of these strategies, the NMDA receptor antagonist memantine is in the most advanced stage of development in the US and is already approved in Europe as the first treatment for moderately severe to severe Alzheimer's disease. Memantine is proposed to counteract cellular damage due to pathological activation of NMDA receptors by glutamate. Results with Ginkgo biloba have been mixed. Data for neurotrophic therapies and vitamin E (tocopherol) appear promising but require confirmation. NSAIDs and conjugated estrogens have not proven to be of value to date for the treatment of Alzheimer's disease. Statins may have a potential role in reducing the risk or delaying the onset of Alzheimer's disease, although this has yet to be confirmed in randomised trials. There are currently no data to support the use of statins as a treatment for dementia. This article provides an update on the current status of selected agents, focusing primarily on those agents with the most extensive clinical evidence at present.
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PMID:Non-cholinergic strategies for treating and preventing Alzheimer's disease. 1242 Nov 15


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