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:3.1.1.8 (cholinesterase)
12,691 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The involvement of the NMDA receptor in the neurotoxicity induced by soman, an organophosphorus compound which irreversibly inhibits cholinesterase, was studied in guinea pigs. The drug MK-801 (0.5, 1 or 5 mg/kg, i.p.) was given as a pretreatment before a convulsant dose of soman or as a posttreatment (30, 100 or 300 micrograms/kg, i.m.) 5 min after the development of soman-induced status epilepticus. Pyridostigmine, atropine and pralidoxime chloride were also given to each subject to counteract the lethality of soman. All subjects that were challenged with soman and given the vehicle for MK-801 (saline) exhibited severe convulsions and electrographic seizure activity. Neuronal necrosis was found in the hippocampus, amygdala, thalamus and the pyriform and cerebral cortices of those subjects surviving for 48 hr. Pretreatment with 0.5 or 1 mg/kg doses of MK-801 did not prevent nor delay the onset of seizure activity but did diminish its intensity and led to its early arrest. At the largest dose (5 mg/kg), MK-801 completely prevented the development of seizure activity and brain damage. Posttreatment with MK-801 prevented, arrested or reduced seizure activity, convulsions and neuronal necrosis in a dose-dependent manner. The NMDA receptor may play a more critical role in the spread and maintenance, rather than the initiation of cholinergically-induced seizure activity.
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PMID:Dizocilpine (MK-801) arrests status epilepticus and prevents brain damage induced by soman. 152 53

The action of tetrahydroaminoacridine (THA), a centrally active cholinesterase inhibitor that may provide symptomatic benefit in Alzheimer's disease, was studied on responses to the excitatory amino acid N-methyl-D-aspartate (NMDA) in cultured hippocampal neurons, using whole-cell voltage-clamp and single-channel recording techniques. THA produced a concentration-dependent block of NMDA-evoked inward current responses (IC50, 190 microM at -60 mV), without affecting responses to quisqualate or kainate. THA block of NMDA responses was voltage dependent and was nearly completely relieved at positive holding potentials. Analysis of the voltage dependency indicated that the THA binding site senses 56% of the transmembrane electrostatic field. In single-channel recordings from outside-out membrane patches, THA appeared to reduce the frequency and duration of NMDA-evoked single-channel currents, without affecting the single-channel amplitude. The effects of THA on NMDA responses occur at concentrations 1-2 orders of magnitude greater than the therapeutic serum concentrations and, therefore, blockade of NMDA receptor-mediated responses is unlikely to contribute to the putative therapeutic action of THA. However, because NMDA receptors may play a critical role in cognitive and memory function, THA has the potential to produce undesirable central nervous system side effects at high doses.
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PMID:Tetrahydroaminoacridine block of N-methyl-D-aspartate-activated cation channels in cultured hippocampal neurons. 170 20

Cultured striatal neurons containing either NADPH-diaphorase or acetylcholinesterase were more resistant to injury by N-methyl-D-aspartate (NMDA) or quinolinate, than the general striatal neuronal population, although this resistance was not absolute and could be overcome by intense toxic exposure. Neurons containing NADPH-diaphorase, but not neurons containing acetylcholinesterase, also exhibited heightened vulnerability to injury by kainate. Given recent evidence that diaphorase- and cholinesterase-containing striatal neurons are selectively spared in Huntington's disease, our results strengthen the possibility that NMDA receptor-mediated neurotoxicity may participate in the pathogenesis of that disease.
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PMID:Cultured striatal neurons containing NADPH-diaphorase or acetylcholinesterase are selectively resistant to injury by NMDA receptor agonists. 283 34

Addition of the acetylcholinesterase inhibitor 1,2,3,4-tetra-9-hydroaminoacridine (THA) at 1-3 mM markedly reduced the neuronal cell loss that otherwise followed brief exposure of murine cortical cell cultures to 500 microM N-methyl-D-aspartate (NMDA). This novel antagonism was selective for NMDA receptor-mediated toxicity, as it extended to glutamate toxicity but not to quisqualate toxicity, and was THA concentration-dependent between 100 microM and 3 mM, with IC50 approximately 500 microM. The antagonism was probably not due to enhancement of endogenous cholinergic action, as it was not mimicked by acetylcholine, carbachol, or bethanechol; rather, it likely reflected a recently described interaction of THA with the phencyclidine receptor. Exploration of structural specificity revealed some partial neuron-protection with high concentrations of other cholinesterase inhibitors--physostigmine, neostigmine, and edrophonium, but not the structurally related potassium channel blocker, 4-aminopyridine. Further examination of correlations between THA-like structure, and neuron-protective activity, may provide useful insights in the development of new antagonists of NMDA receptor-mediated neurotoxicity.
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PMID:Tetrahydroaminoacridine selectively attenuates NMDA receptor-mediated neurotoxicity. 290 64

The Stone maze paradigm has been developed for use as a rat model of memory impairment observed in normal aging and in Alzheimer's disease. Results from several studies have demonstrated the involvement of both cholinergic and glutamatergic systems in acquisition performance in this complex maze task. Although results of clinical studies on the cognitive enhancing abilities of cholinomimetics for treatment of memory impairment in Alzheimer's disease have been inconsistent, new classes of cholinesterase inhibitors offer greater potential for therapeutic efficacy. The physostigimine derivative, phenserine, appears to have marked efficacy for improving learning performance of aged rats or of young rats treated with scopolamine in the Stone maze. Declines in markers of glutamatergic neurotransmission in Alzheimer's disease and in normal aging suggest that pharmacological manipulation of this system might also prove beneficial for cognitive enhancement. Treatment with glycine and/or polyamine agonists is suggested as a strategy for activating the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor. In addition, the use of combined pharmacological activation of cholinergic and glutamatergic systems is suggested. Manipulation of signal transduction events should also be considered as a strategy for cognitive enhancement. The influx of Ca2+ through the channel formed by the NMDA receptor stimulates the production of the oxyradical, nitric oxide (NO*), via the action of nitric oxide synthase (NOS). Compounds that inhibit NOS activity impair acquisition in the Stone maze, suggesting an involvement of NO*. Thus, strategies for inducing NO* production to enhance cognitive performance may be beneficial. Because of the potential neurotoxicity for NO*, this strategy is not straightforward. Although many new directions beyond the cholinergic hypothesis can be suggested, each has its potential benefits which must be weighed against its risks. Nonetheless, an important unifying area for neurobiological research examining mechanisms of normal brain aging and of age-related neuropathology, as observed in Alzheimer's disease, might emerge from the identification of NO* as a simple molecule serving vital physiological functions but representing potential for neurotoxicity.
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PMID:Rodent models of memory dysfunction in Alzheimer's disease and normal aging: moving beyond the cholinergic hypothesis. 799 63

We have developed the Stone maze paradigm for use as a rat model of memory impairment observed in normal aging and in Alzheimer's disease. Evidence produced thus far clearly implicates both the cholinergic and glutamatergic systems in acquisition performance in this complex maze task. Although results have been very inconsistent regarding the cognitive enhancing abilities of cholinomimetics for use in Alzheimer's disease, new classes of cholinesterase inhibitors may offer greater therapeutic efficacy. The use of glycine and polyamine agonists appears to be a viable strategy for positive modulation of the NMDA receptor. In addition, an approach that combines stimulation both of cholinergic and glutamatergic systems may have greater potential than agonism of either separately. Manipulation of signal transduction events might also have potential for cognitive enhancement. The influx of Ca2+ through the NMDA receptor stimulates production of NO via the action of NOS. By using NARG to block NOS activity, we have demonstrated in rats that NO production appears to influence learning in the Stone maze. We are currently exploring the age-related changes in NOS activity in specific brain regions of rats to determine if loss in the NO generating system is related to age-related memory impairment observed in the Stone maze. In addition, we are exploring pharmacological strategies for inducing NO production; however, because of the potential neurotoxicity for NO overstimulation, this strategy will present some obstacles. The identification of NO as a simple molecule serving vital physiological functions but representing potential for neurotoxicity presents an important unifying area for neurobiological investigations searching for mechanisms of normal brain aging and of age-related neuropathology, as observed in Alzheimer's disease.
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PMID:New pharmacological strategies for cognitive enhancement using a rat model of age-related memory impairment. 803 Aug 31

The muscarinic receptor antagonist scopolamine significantly increased the number of errors in the working memory task with a three-panel runway setup, when injected bilaterally at 3.2 micrograms/side into the dorsal hippocampus. The increase in working memory errors induced by intrahippocampal 3.2 micrograms/side scopolamine was reduced by concurrent injection of the cholinesterase inhibitor physostigmine (1.0 and 3.2 micrograms/side. However, physostigmine (3.2 micrograms/side) did not affect an increase in working memory errors induced by intrahippocampal injection of the competitive N-methyl-D-aspartate (NMDA) receptor antagonist (+/)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) at 32 ng/side. Likewise, physostigmine (3.2 micrograms/side) was ineffective in reducing an increase in working memory errors caused by intrahippocampal administration of the 5-hydroxytryptamine1A (5-HT1A) receptor agonist (+/-)-8-hydroxy-2-(di-n-pro-pylamino)tetralin (8-OH-DPAT) at 10 micrograms/side. These results suggest that the septohippocampal cholinergic activity is necessary for normal working memory processes, but that cholinergic activation neither compensates loss of hippocampal NMDA receptor-mediated neurotransmission nor counteracts the overstimulation of hippocampal 5-HT1A receptors in terms of working memory function.
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PMID:Effect of cholinergic activation by physostigmine on working memory failure caused in rats by pharmacological manipulation of hippocampal glutamatergic and 5-HTergic neurotransmission. 890 30

INTRAHIPPOCAMPAL administration of the muscarinic acetylcholine receptor antagonist scopolamine at a dose of 3.2 micrograms/side significantly increased the number of errors (attempts to pass through two incorrect panels of the three panel-gates at four choice points) in the working memory task with a three-panel runway setup, whereas 0.32 microgram/side scopolamine did not affect working memory errors. The beta-adrenoceptor antagonist propranolol (10 mg/kg, i.p.) had no effect on working memory error, but it produced a significant increase in working memory errors when administered in combination with intrahippocampal scopolamine at the behaviourally ineffective dose (0.32 microgram/side). The increase in working memory errors induced by intrahippocampal administration of 0.32 microgram/side scopolamine to rats treated with 10 mg/kg propranolol was decreased by concurrent injection of the cholinesterase inhibitor physostigmine (3.2 micrograms/side). D-Cycloserine (the partial agonist at the glycine bindings site on the NMDA receptor/channel complex) at a dose of 10 micrograms/side reduced the increase in working memory errors induced by intrahippocampal 0.32 microgram/side scopolamine combined with 10 mg/kg propranolol. These results suggest that neural mechanisms regulated cooperatively by hippocampal muscarinic and beta-adrenergic transmission underlie working memory performance, and that modification of NMDA function contributes to such interactive regulation of working memory processes in the hippocampus.
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PMID:Working memory failure by combined blockade of muscarinic and beta-adrenergic transmission in the rat hippocampus. 918 94

Effects of soman, an irreversible cholinesterase (ChE) inhibitor, on [3H]norepinephrine (NE) release evoked by N-methyl-d-aspartate (NMDA) were studied in rat brain cortical slices. Soman inhibited NMDA-stimulated [3H]NE release in a concentration-dependent manner. This effect was neither reversed by atropine, an antagonist of the muscarinic receptor, nor by d-tubocurarine, an antagonist of the nicotinic receptor. Incubation of the slices with NMDA antagonists, AP5, MK-801, ketamine or magnesium, resulted in inhibitory effects on NMDA-stimulated [3H]NE release. Soman significantly shifted the inhibition curves downward and significant interactions between these chemicals and soman were observed. Glycine potentiated the release of [3H]NE stimulated by NMDA, and soman did not alter this effect of glycine. Soman also inhibited the release of [3H]NE evoked by K+ in a concentration-dependent manner. NMDA-stimulated [3H]NE release was inhibited by tetrodotoxin (TTX), an antagonist of voltage-dependent sodium channels, and a significant interaction between soman and TTX was observed. The [3H]NE release induced by NMDA was dependent on extracellular calcium concentrations and was inhibited by nifedipine, a selective blocker of the L-type voltage-dependent calcium channels (VDCC), or cadmium, a non-specific blocker of VDCC. However, no significant interaction between the effects of soman and calcium, nifedipine, or cadmium was observed. Taken together, the results suggested that: (1) soman has a direct action at non-cholinergic sites; (2) soman may interfere with some of the regulatory sites of the NMDA receptor-ion channel complex; and (3) the voltage-dependent sodium channel, but not VDCC, may be a site of action for soman.
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PMID:Inhibition by soman of NMDA-stimulated [3H]norepinephrine release from rat cortical slices, studies of non-cholinergic effect. 951 77

We investigated the effect of tetrahydroaminoacridine, a cholinesterase inhibitor and D-cycloserine (a partial glycine-B agonist of the NMDA receptor complex) on the defect of water maze spatial navigation in rats induced by aging. Tetrahydroaminoacridine (3 mg/kg, i.p.) or D-cycloserine (10 mg/kg, i.p.) enhanced acquisition of the water maze task. A combination of subthreshold doses of tetrahydroaminoacridine (1 mg/kg) and D-cycloserine (3 mg/kg) improved water maze acquisition, but a combination of lower subthreshold doses (tetrahydroaminoacridine 0.3 mg/kg + D-cycloserine 1 mg/kg) was ineffective. Consolidation in water maze test was not improved by tetrahydroaminoacridine (3 mg/kg) and/or D-cycloserine (10 mg/kg). The results suggest that tetrahydroaminoacridine and D-cycloserine synergistically enhance acquisition of spatial navigation in aged rats.
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PMID:Tetrahydroaminoacridine and D-cycloserine stimulate acquisition of water maze spatial navigation in aged rats. 954 87


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