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)

The pattern of ischemia-induced cell death was examined with histochemical methods in the striatum of adult gerbils 4 and 7 days after transient forebrain ischemia. The results showed a massive loss of immunoreactivity to enkephalin and tachykinins, peptides present in striatal efferent neurons. In contrast, neurons expressing acetylcholinesterase activity, or choline acetyltransferase immunoreactivity, as well as neurons immunoreactive for somatostatin, were relatively preserved in areas of severe neuronal loss. The selective vulnerability of subpopulations of striatal neurons to transient ischemia in the adult is similar to that observed in the neonate and after local injections of agonists of N-methyl-D-aspartate receptors, but not of agonists of other glutamate receptor subtypes. It also presents striking similarities to the pattern of neuronal death observed in Huntington's disease. The results further support a role for overstimulation of a subtype of excitatory amino acid receptor in ischemia-induced cell death and show that the selective sparing of subpopulations of striatal interneurons after ischemic injury is not related to immaturity of these neurons but also occurs in the adult.
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PMID:Ischemic damage in the striatum of adult gerbils: relative sparing of somatostatinergic and cholinergic interneurons contrasts with loss of efferent neurons. 197 9

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

We measured cholinergic markers and acetylcholinesterase (AChE) molecular forms after glutamate receptor stimulation of superfused slices of mouse spinal cord at different developmental ages. AChE globular forms were secreted in a dose-dependent fashion. A period of selective sensitivity to excitotoxic agents was detected by increased acetylcholine (ACh) release and AChE secretion (sAChE) at postnatal day 14. Strychnine-resistant glycine stimulation potentiated glutamate-induced AChE release, suggesting N-methyl-D-aspartate (NMDA) receptor involvement.
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PMID:Excitotoxicity and cholinergic chemical markers during programmed motor neurone death. 780 41

The present study was undertaken to study the interaction of cholinergic and glutamatergic mechanisms in cholinoceptive cortical target regions which is 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, as well as NMDA, AMPA and kainate glutamate receptor subtypes were measured in rats one week after unilateral mechanical lesion of the anterior part of the nucleus basalis magnocellularis (NbM) applying quantitative receptor autoradiography and in situ hybridization. The studies revealed that in cortical regions displaying a low amount of acetylcholinesterase activity due to forebrain cholinergic lesion, NMDA receptor binding was markedly reduced in comparison to the unlesioned side, whereas AMPA and kainate binding has been significantly increased in these regions. M1-muscarinic cholinergic receptor binding was not changed in any of the cortical regions studied, whereas M2-receptor densities are slightly reduced in frontal and parietal cortices following lesion. These alterations in cortical M2-muscarinic receptor binding are complemented by corresponding changes in the m2- and m4-mRNA transcripts. The comparison of binding profiles through selected cortical regions of both lesioned and normal brain side revealed that lesion of the NbM affects NMDA receptors in all cortical layers of the lesioned side, whereas AMPA receptors are affected preferentially in the upper and kainate receptors preferentially in the middle and deeper cortical layers. The differential changes in glutamate 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 glutamatergic functions with different intensity and different directions.
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PMID:Receptor function in cortical rat brain regions after lesion of nucleus basalis. 789 91

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

The levels of choline acetyltransferase (ChAT) and the binding activity of N-methyl-D-aspartate (NMDA) and non-NMDA receptors have been measured in the hippocampus, entorhinal cortex, frontal cortex and cerebellum, in a series of human brains from 24 weeks gestation to 100 years. The patterns of ChAT and glutamate receptor activity during aging and development were strikingly different in the different brain areas. In the hippocampus and associated cortex, ChAT activity did not reach a peak until middle age, when it almost immediately started to decline by 50-60% to the 10th decade, whereas in the frontal cortex ChAT peaked transiently in the infant and then stayed constant during aging. In the cerebellum ChAT activity was very high in the foetus and fell in the neonate to maintain a constant level more in line with the concentrations found in the other brain areas through the rest of life. The high levels of ChAT in the foetal cerebellum were not associated with high acetylcholinesterase (AChE) content, which tended to increase during development, and was present initially in Purkinje cells (foetus and neonate) and the molecular layer in the adult. In the hippocampus and entorhinal cortex, autoradiographic [3H]MK-801 binding was relatively constant throughout life, however, [3H]CNQX binding rose from the perinatal period up to a peak in the 1st or 2nd decade and then tended to fall with age. In the cerebellum, autoradiographic binding of both ligands rose from the foetal period to reach a plateau by the age of 10 years and there was no apparent further change during aging. These data on cholinergic and glutamatergic phenotypic changes during development and senescence reflect marked variations in regional plasticity and aging within and between the two transmitter systems and are likely to contribute to our understanding of their role in the different brain areas investigated.
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PMID:Regional patterns of cholinergic and glutamate activity in the developing and aging human brain. 810 41

Whole-cell voltage-clamp recordings were used to study excitatory amino acid-induced currents in neurons isolated from the septum of fetal rat brains. The neurons were cultured for more than four weeks on a feeder layer composed of glial cells obtained from the septal region. Septal neurons were either fusiform, triangular or multipolar and 83% of cells showed acetylcholinesterase activity. L-Glutamate, kainate, quisqualate and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) applied by local perfusion produced inward currents (Iglu, Ikai, Iquis and IAMPA, respectively) at -44mV which increased in amplitude with increasing concentration of agonist; they desensitized when induced at higher concentrations except for the Ikai. The EC50s for the peak Ikai and sustained Iglu, Iquis and IAMPA were 55, 13, 0.39 and 3.5 microM, respectively. 6-Cyano-7-nitroquinoxaline-2,3-dione (CNQX) depressed Ikai and IAMPA evoked at a concentration of 10 microM (IC50s: 0.58 and 0.84 microM, respectively). Schild analysis for the CNQX action on Ikai gave a dissociation constant of 0.27 microM for CNQX. n-Methyl-D-aspartate (NMDA) (with glycine, 3 microM) produced an inward current (INMDA) at -44 mV whose peak amplitude enhanced with increased concentrations (EC50 = 32 microM). INMDA was potentiated by glycine (EC50 = 0.15 microM) and inhibited by D-2-amino-5-phosphovalerate (IC50 = 9.9 microM for INMDA evoked at a concentration of 50 microM). MK-801 (0.1-10 microM) inhibited INMDA in a dose- and use-dependent manner. INMDA was (0.1-10 microM) inhibited INMDA in a dose- and use-dependent manner. INMDA was potentiated by spermine (EC50 = 247 microM; 91% increase at 1mM) in a manner independent of holding potential (VH). INMDA was inhibited by Mg2+ and Zn2+ (IC50 = 673 and 39 microM, respectively, at -44 mV) in a manner dependent on VH; the magnitudes of a depolarization required for an e-fold increase in their IC50s in a range of -64 to -24 mV were 16 and 22 mV, respectively. The action of Zn2+ was independent of VH > -24 mV. Current-voltage relations for Ikai, Iquis and IAMPA exhibited outward rectification, while that of INMDA showed a region of negative conductance at VH < -30 mV, which disappeared in a Mg(2+)-free solution. Reversal potentials for Ikai, Iquis, IAMPA and INMDA were close to 0 mV, indicating the involvement of non-specific cation channels. Increasing extracellular Ca2+ concentration from 2.4 to 30 mM did not affect the Ikai and Iquis, reversal potential showing negligible Ca2+ component, but shifted INMDA reversal potential to a more positive potential, yielding a ratio of Ca2+ permeability to that of monovalent cation to be 13. Cholinergic septal neurons in culture express non-NMDA-(AMPA/kainate-) and NMDA-type of glutamate receptor channels. Their properties were quantitatively similar to those of glutamate receptor channels on other types of neurons in the brain except for the actions of endogenous neuromodulators (Mg2+, Zn2+ and spermine) on NMDA receptor channels. It is suggested that NMDA receptor channels on different types of neurons may play a distinct role depending on a difference in the actions of these neuromodulators.
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PMID:Excitatory amino acid-induced currents in rat septal cholinergic neurons in culture. 855 43

To study the effect of reduced cortical cholinergic activity on GABAergic and glutamatergic mechanisms in cholinoceptive cortical target regions a novel cholinergic immunotoxin (conjugate of the monoclonal antibody 192IgG against the low-affinity nerve growth factor receptor with the cytotoxic protein saporin) was applied, which specifically and selectively destroys cholinergic cells in rat basal forebrain nuclei. To correlate the responses to cholinergic immunolesion in cholinoceptive cortical target regions with cholinergic hypoactivity, quantitative receptor autoradiography to measure NMDA, AMPA and kainate glutamate receptor subtypes, GABAA and benzodiazepine receptors as well as choline uptake sites, and histochemistry to estimate acetylcholinesterase activity were performed in adjacent brain sections. One week after a single intraventricular injection of 4 micrograms of 192IgG-saporin, NMDA receptor binding was markedly reduced in cortical regions displaying a reduced activity of acetylcholinesterase and high-affinity choline uptake sites as a consequence of cholinergic lesion, whereas AMPA and kainate binding sites were significantly increased in these regions. Muscimol binding to GABAA receptors was increased in the caudal portions of frontal and parietal cortices as well as occipital and temporal cortex as compared to the corresponding brain regions from vehicle-injected control rats. 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 cholinergic immunolesion 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:192IgG-saporin-induced immunotoxic lesions of cholinergic basal forebrain system differentially affect glutamatergic and GABAergic markers in cortical rat brain regions. 857 66

The superior colliculus is a midbrain structure serving visual, multisensory and sensorimotor processing. Throughout various collicular layers, visual afferents are linked together with afferents related to other sensory modalities as well as with afferents from sources not easily subsumed under the term 'sensory'. These inputs are orchestrated in a topographic fashion and led to premotor neurons that are important elements in generating saccadic eye movements and orientation movements of other kinds. Using immunocytochemical techniques to chart the distribution of various substances serving neurotransmission and neuromodulation, it was found that many of them, e.g. acetylcholinesterase (AChE), choline acetyltransferase, the enkephalins, substance P, and parvalbumin, relate to repetitive structural islands, or modules, in the superior colliculus. From studies on the distribution of three further neuroactive substances in rat superior collicular tissue: the calcium binding protein calretinin, the growth and plasticity related protein neuromodulin (GAP-43), and a glutamate receptor of the NMDA-type, we were led to conclude (1) that the intermediate layers of the superior colliculus are composed not of two, but of at least three disjunct types of modules, (2) that not just the intermediate layers but more or less the whole superior colliculus is an assemblage of modules, and (3) that, besides topographic connectivity and laminar structuring, the modules constituting an iterative partitioning represent a third major feature of superior collicular architecture. The origin of the collicular mosaic is considered under an evolutionary perspective, and a hypothesis is presented stating that the pattern of AChE-rich modules on the level of the multimodal collicular layers can be predicted from retinal ganglion cell topography.
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PMID:The mosaic architecture of the superior colliculus. 897 18

Although some promising results have been achieved by acetylcholinesterase inhibitors, an effective therapeutic intervention in Alzheimer's disease still remains an important goal. Sitoindosides VII-X, and withaferin-A, isolated from aqueous methanol extract from the roots of cultivated varieties of Withania somnifera (known as Indian Ginseng), as well as Shilajit, a pale-brown to blackish brown exudation from steep rocks of the Himalaya mountain, are used in Indian medicine to attenuate cerebral functional deficits, including amnesia, in geriatric patients. The present investigation was conducted to assess whether the memory-enhancing effects of plant extracts from Withania somnifera and Shilajit are owing to neurochemical alterations of specific transmitter systems. Therefore, histochemistry to analyse acetylcholinesterase activity as well as receptor autoradiography to detect cholinergic, glutamatergic and GABAergic receptor subtypes were performed in brain slices from adult male Wistar rats, injected intraperitoneally daily with an equimolar mixture of sitoindosides VII-X and withaferin-A (prepared from Withania somnifera) or with Shilajit, at doses of 40 mg/kg of body weight for 7 days. Administration of Shilajit led to reduced acetylcholinesterase staining, restricted to the basal forebrain nuclei including medial septum and the vertical limb of the diagonal band. Systemic application of the defined extract from Withania somnifera, however, led to differential effects on AChE activity in basal forebrain nuclei: slightly enhanced AChE activity was found in the lateral septum and globus pallidus, whereas in the vertical diagonal band AChE activity was reduced following treatment with sitoindosides VII-X and withaferin-A. These changes were accompanied by enhanced M1-muscarinic cholinergic receptor binding in lateral and medial septum as well as in frontal cortices, whereas the M2-muscarinic receptor binding sites were increased in a number of cortical regions including cingulate, frontal, piriform, parietal and retrosplenial cortex. Treatment with Shilajit or the defined extract from Withania somnifera affected neither GABAA and benzodiazepine receptor binding nor NMDA and AMPA glutamate receptor subtypes in any of the cortical or subcortical regions studied. The data suggest that Shilajit and the defined extract from Withania somnifera affect preferentially events in the cortical and basal forebrain cholinergic signal transduction cascade. The drug-induced increase in cortical muscarinic acetylcholine receptor capacity might partly explain the cognition-enhancing and memory-improving effects of extracts from Withania somnifera observed in animals and humans.
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PMID:Systemic administration of defined extracts from Withania somnifera (Indian Ginseng) and Shilajit differentially affects cholinergic but not glutamatergic and GABAergic markers in rat brain. 901 65


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