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At least 883 records · Page 49Linked to original sources
PubMed1994

Characterization of a novel muscarinic receptor agonist, YM796: comparison with cholinesterase inhibitors in in vivo pharmacological studies.

Previous reports have shown that (+/-)-YM796 (2,8-dimethyl-3-methylene-1-oxa-8-azaspiro[4.5]decane) exhibits M1 agonistic activity and ameliorates cognitive impairment, and that the (-)-S isomer is active in in vitro studies. We report here the characterization of the (-)-S isomer, YM796 ((-)-(S)-2,8-dimethyl-3-methylene-1-oxa-8-azaspiro[4.5]decane L-tartrate monohydrate), and its (+)-R isomer in in vivo pharmacological studies in comparison with the cholinesterase inhibitors tacrine, amiridine and E-2020. YM796 (0.031-0.5 mg/kg p.o.), like the racemate, reversed the cognitive impairment in passive avoidance tasks of rats with nucleus basalis magnocellularis lesions, whereas (+)-R-YM796 was ineffective in this experimental amnesia. YM796 exhibited only weak effects on mouse salivation and hypothermia, a peripheral cholinergic response and a central cholinergic response, respectively. The (+)-R isomer, however, failed to induce these cholinergic responses. YM796 also ameliorated the memory deficits induced by scopolamine in rats and electroconvulsive shock in mice. The potency of YM796 in these experimental amnesia models was over a 100 times greater than that of tacrine, over 10 times greater than that of E-2020, and 6 times greater than that of amiridine. In salivary secretion and hypothermia, YM796 was 2-4 times weaker than tacrine and E-2020, and 1-2 times stronger than amiridine. Thus, YM796's ratio of anti-amnesic effects to salivary secretion and hypothermia was much greater than that of the cholinesterase inhibitors tested.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Reduced cholinesterase activity and somatostatin-like immunoreactivity in the cerebrospinal fluid of patients with dementia of the Alzheimer type.

Cholinesterase (ChE) activity and somatostatin-like immunoreactivity (SLI) of the cerebrospinal fluid were determined for 59 patients with dementia of the Alzheimer type (AD/SDAT) and for 19 age-matched control patients with no signs of dementia. Both ChE activities and SLI concentrations of cerebrospinal fluid were reduced significantly in dementia patients compared to the controls. In the AD/SDAT patients cholinesterase and somatostatin-like immunoreactivity levels seemed to be correlated with the severity of dementia. These findings agree with observations of reduced cortical acetylcholinesterase activities and somatostatin values in dementia of the Alzheimer type.

Aged↗
PubMed1986

Cholinesterases in cerebrospinal fluid. Correlations with clinical measures in Alzheimer's disease.

Acetylcholinesterase and butyrylcholinesterase activities in cerebrospinal fluid were measured in 17 patients with Alzheimer's disease and 6 control patients, as potential clinical measures of impaired cholinergic neurotransmission in Alzheimer's disease. The activity of butyrylcholinesterase was decreased in patients with Alzheimer's disease compared to that observed in control patients, but there was overlap between values in the 2 groups. Low butyrylcholinesterase activity was correlated with severity of dementia, memory impairment, and language disorder. Acetylcholinesterase activity was significantly correlated with visual contrast sensitivity, but not with dementia severity, and did not differentiate patients with Alzheimer's disease from control cases. These results suggest that cholinesterases in cerebrospinal fluid are related to brain cholinesterases, and indicate that the activities of acetylcholinesterase and butyrylcholinesterase should be distinguished in studies of cerebrospinal fluid.

Acetylcholinesterase↗
PubMed1985

A quaternary anti-cholinesterase probe for determining the integrity of the blood--brain barrier.

7-(Methylethoxyphosphinyloxy)-1-methyl quinolinium iodide (MEPQ), a new quaternary anti-cholinesterase (anti-ChE) compound was prepared and evaluated as a potential probe for assessing changes in the blood-brain barrier (B-BB) permeability. MEPQ was found to be 170 times more potent in its cholinesterase inhibitory activity than phospholine iodide, a previously reported anti-ChE probe in B-BB research. In rats and mice with impaired B-BB induced by osmotic opening, MEPQ readily penetrated through the damaged site as demonstrated by considerable reduction of ChE activity. In controls, brain ChE activity remained unaffected. It is suggested that MEPQ is a useful probe for both qualitative (histological staining) and quantitative (brain homogenated) assessment of permeability changes in the B-BB.

Animals↗
PubMed1993

A paradoxical stimulatory effect of berberine on guinea-pig ileum contractility: possible involvement of acetylcholine release from the postganglionic parasympathetic nerve and cholinesterase inhibition.

The effects of berberine on guinea-pig ileum contractility were studied in both transmurally-stimulated and unstimulated preparations. Transmural stimulation (80 V, 0.5 ms, 0.05 Hz) of the guinea-pig ileal segments produced a twitch response. Berberine (10(-8)-10(-5) M) enhanced this response dose-dependently. Atropine (10(-7) M), but not mecamylamine (10(-5) M), abolished this response. Acetylcholine (3 x 10(-9) and 10(-8) M) also enhanced the response to transmural stimulation. Pretreatment with hemicholinium (3 x 10(-5) M) antagonized the effect of berberine but failed to change that of acetylcholine. Berberine (10(-5) M) also antagonized the alpha 2-adrenoceptor agonist xylazine (10(-8) and 10(-7) M)-induced inhibition of the twitch response to transmural stimulation. In unstimulated ileal preparations, berberine (10(-5) M) produced contractile responses. In these preparations, atropine (10(-6) M), but not mecamylamine (10(-4) M), abolished the response to berberine. Furthermore, berberine (10(-6)-10(-4) M) inhibited dose-dependently the cholinesterase activity of the guinea-pig blood. The results suggest that berberine increases ileal contractility by: 1) increasing acetylcholine release from the postganglionic parasympathetic nerve terminal, 2) increasing acetylcholine retention through an inhibition of cholinesterase activity, and 3) blocking alpha 2-adrenoceptors, possibly in the postganglionic parasympathetic nerve.

Acetylcholine↗
PubMed1984

Comparison of measurement of dialkyl phosphates in milk/urine and blood cholinesterase and insecticide concentrations in goats exposed to the organophosphate insecticide, imidan.

Recognition of exposure to imidan was assessed in goats by dialkyl phosphate concentrations, blood cholinesterase (ChE) determinations, and blood imidan concentrations. Groups of three goats received 5.0 mg imidan/kg/day (low dose) or 10 mg imidan/kg/day (high dose) for 7 days orally. One goat received no imidan and one goat received an acute single dose (200 mg/kg). The urine of all treated goats was examined for the excretory dialkyl phosphates, O,O-dimethyl phosphorodithioate (DMDTP) and O,O-dimethyl phosphorothionate (DMTP). The overall mean DMDTP urinary concentration was 19.1 ppm (10-mg/kg treatment group) and 7.2 ppm (5-mg/kg treatment group). These metabolites rapidly disappeared following removal of the treatment except in those goats clinically affected. Milk contained no identifiable concentrations of dialkyl phosphates. Cholinesterase depression was observed in all imidan-treated goats, and a dose effect was observed. No imidan was detected in whole blood of either the 5- or 10-mg/kg treatment groups. Low blood concentrations (ppb) of imidan were measured in the acute single-dose exposed goat. Both urinary DMDTP and blood ChE provided recognition of imidan exposure. DMDTP, however, was immediately present in urine after exposure and provided stronger support for organophosphate exposure than did blood ChE.

Animals↗
PubMed1993

Discriminative stimulus properties of NIK-247 and tetrahydroaminoacridine, centrally active cholinesterase inhibitors, in rats.

The discriminative stimulus effect of the novel centrally active cholinesterase inhibitor, NIK-247, was investigated in rats and compared with that of tetrahydroaminoacridine (THA). Rats were trained to discriminate either 10 mg/kg NIK-247 or 1.8 mg/kg THA from saline in a two-lever food-reinforced procedure. The stimulus effect of NIK-247 was substituted for by the cholinesterase inhibitors, THA and physostigmine. The THA stimulus was substituted for by NIK-247 and physostigmine. The muscarinic receptor agonist arecoline substituted for the NIK-247 and THA stimuli. Both stimulus effects of NIK-247 and THA were blocked by the muscarinic antagonist scopolamine. The dopaminergic-activating drugs amantadine and lisuride substituted for the stimulus effects of NIK-247 and THA. However, neither the NIK-247 nor the THA stimulus was antagonized by the dopamine antagonists haloperidol, SCH 23390, and sulpiride. These results suggest that the discriminative stimulus effects of NIK-247 and THA are mediated by muscarinic receptors, and that the dopaminergic activity resulting from cholinergic activation may account for some part of both stimuli.

Aminoquinolines↗
PubMed1988

Development of 'non-specific' cholinesterase-containing neurons in the dorsal thalamus of the rat.

In adult rats, neurons displaying histochemical staining for 'non-specific' cholinesterase (ChE) are found 3 distinct regions of the dorsal thalamus: the thalamic reuniens nucleus (Re), the anterior dorsal nucleus (AD), and a region that includes the lateral part of the central lateral nucleus (CL) and the ventral portion of the lateral dorsal nucleus (LD). Normal development of ChE-positive neurons was studied with cholinesterase histochemical techniques in postnatal infant rats. Although ChE staining of capillary endothelium is detectable shortly after birth, ChE staining of neurons first occurs at about postnatal day 5 (PND 5) with light staining of AD and CL-LD. At PND 7, staining in AD and CL-LD has increased in intensity and staining also is present in neurons of the anterior ventral (AV) and ventral anterior (VA) nuclei. ChE staining of neurons in Re first appears at PND 10. The number of neurons staining for ChE in each of these nuclei, and also the intensity of staining in individual neurons, appear to increase during the next several days until about PND 14. After PND 14, ChE staining intensity in neurons of AD, Re, and CL-LD appears to plateau and the pattern of staining continues into adulthood. In contrast, ChE staining of neurons in VA declines markedly and only a very few neurons in the dorsal part of VA remain ChE-positive after PND 21. ChE staining of neuropil in AV increases markedly, obscuring somatal staining in this nucleus. These results are discussed in regard to transient and continued expression of ChE activity in the dorsal thalamus and possible functional roles of ChE.

Acetylcholinesterase↗
PubMed1996

Lewy-body dementia and responsiveness to cholinesterase inhibitors: a paradigm for heterogeneity of Alzheimer's disease?

The concept of heterogeneity of Alzheimer's disease is based on molecular, neuropathological, clinical and neuropsychological features, and also supported by the observation that Alzheimer's patients differ in their response to pharmacological interventions. Recent investigations evaluating the therapeutic potential of cholinesterase inhibitors have disclosed the existence of at least two subsets of patients with dementia, defined as 'responders' and 'nonresponders' to this therapy. In this article, Paolo Liberini and colleagues suggest that the cluster of responders to the cholinesterase inhibitors might include a significant number of subjects with a rather selective dysfunction of the cholinergic system, as in the case of Lewy-body dementia. A neuropathological demonstration of this correlation should open up new therapeutic perspectives.

Alzheimer Disease↗
PubMed1991

On the inhibition of cholinesterase by D-tubocurarine.

Some investigation in this laboratory pointed to an unexpectedly slow inhibition of cholinesterase by D-tubocurarine, occurring in addition to a typically instantaneous inhibition. In order to elucidate this phenomenon, the hydrolysis of butyrylthiocholine catalyzed by cholinesterase was recorded, in the absence and presence of D-tubocurarine, on a stopped-flow apparatus. Experimental results were analyzed by classical kinetic methods and by means of mathematical modeling. It was found that the inhibition is of a double character, consisting of an instantaneous phase and a slow one occurring in a minute time scale. It seems that the action of D-tubocurarine is a consequence of an instantaneous binding of D-tubocurarine to a peripheral site, followed by a relatively slow conformational transition in the enzyme.

Butyrylthiocholine↗
PubMed1989

Effect of scopolamine and HP 029, a cholinesterase inhibitor, on long-term potentiation in hippocampal slices of the guinea pig.

The effect of scopolamine and a cholinesterase inhibitor on long-term potentiation (LTP) of population spikes was studied in a guinea pig hippocampal slice preparation. After brief application of each drug (10 min), LTP in CA1 and CA3 was induced by tetanus stimulation delivered to commissural/associational fibers and mossy fibers, respectively. Scopolamine at concentration of 10 microM had no effect on LTP in CA1 but significantly suppressed LTP in CA3. The cholinesterase inhibitor, 9-amino-1,2,3,4-tetrahydroacridine-1-ol maleate (HP 029) at concentration of 10 microM significantly enhanced LTP both in CA1 and CA3. These results suggest that the cholinergic system is involved in producing LTP in CA3. Another mechanism of the effect of HP 029 on LTP in CA1 is discussed.

Action Potentials↗
PubMed1993

Muscarinic receptors mediate attenuation of extracellular acetylcholine levels in rat cerebral cortex after cholinesterase inhibition.

Muscarinic autoregulation of extracellular acetylcholine levels was investigated by microdialysis in the cerebral cortex of freely moving rats under basal conditions as well as following systemic administration of a reversible cholinesterase inhibitor. Atropine (2.2 mg/kg s.c. or 0.2 microM via the dialysis probe) did not affect basal extracellular acetylcholine levels in the cerebral cortex. However, it did potentiate the elevation of extracellular acetylcholine levels produced by a dose of systemic heptylphysostigmine which inhibited 25% of cortical and 40% of plasma cholinesterase activity. These observations suggest that the extracellular concentration of acetylcholine following moderate acetylcholinesterase inhibition is regulated through muscarinic receptors.

Acetylcholine↗
PubMed1993

Ammonia-induced alterations in the activities of synaptosomal cholinesterases of rat brain under in vitro and in vivo conditions.

Effects of in vivo and in vitro pathophysiological concentrations of ammonium acetate were studied on the activities of acetyl and pseudocholinesterases in the synaptosomes isolated from cerebral cortex, cerebellum and brain stem of rat brain. Administration of subacute and acute doses of ammonium acetate elevated the activities of both the cholinesterases in synaptosomes of all the above three regions. A linear relationship (r = 0.98) was observed between brain-ammonia levels and magnitude of elevation in the activities of cerebral cholinesterases. Kinetic analysis revealed that this elevation was due to a change in the Vm but not in the Km of the enzymes. Incubation of synaptosomes isolated from normal animals with 1, 5 and 10 mM ammonium acetate marginally elevated the activities of these enzymes and had no effects on purified enzyme. It is suggested that the changes in the activities might be due to altered architecture of the membranes which exposes more number of catalytic sites.

Acetylcholinesterase↗
PubMed1987

A simple method for the measurement of blood cholinesterase activities under field conditions.

A new separation method using a hand-driven discoidal micro-centrifuge was developed. It is suitable for separating red cells from plasma in field conditions. The amounts of plasma produced are sufficient to be used for the dip-stick estimation of pseudocholinesterase activity. The strip estimations of plasma pseudochoninesterase activity correlated well with the spectrophotometric method of plasma cholinesterase. The test paper methods seem to be reliable under field conditions in acute organophosphate poisonings. To verify the results of the paper strip methods the blood method absorbed on paper can be used. This method is applicable for the measuring of blood cholinesterase activities and thus monitoring humans exposed to organophosphates under field conditions.

Butyrylcholinesterase↗
PubMed1986

Variability of quantal events in control solution and after cholinesterase blockade in frog.

Amplitudes of miniature end-plate currents (AMEPCs) as well as their time constants of decay (TMEPCs) contribute to the amplitudes of miniature end-plate potentials and hence determine their mean values and variability. Larger mean amplitudes of miniature end-plate potentials observed after cholinesterase blockade result from both greater mean AMEPCs and greater mean TMEPCs. However, enhanced variability of amplitudes of miniature end-plate potentials is a result mainly of greater variability of TMEPCs. This occurs almost exclusively because the amplitude dependence of TMEPCs becomes markedly enhanced. Although the scatter of TMEPCs about TMEPC vs AMEPC curve is also larger, it does not contribute much to the increased variability of TMEPCs. The marked amplitude dependence of TMEPCs indicates that repetitive binding strongly depends on the quantal size--the number of acetylcholine molecules released per quantum, and suggests that if a quantum is the result of a release of several vesicles, then they should be released very close to each other. Marked amplitude dependence of TMEPCs also shows that, with cholinesterase inhibited, the quantal size can be estimated not only from AMEPCs, but also from TMEPCs. Greater scatter of TMEPCs from the TMEPC vs AMEPC curve is of more obscure origin and probably results because repetitive binding occurs over enlarged "critical areas" with more variable density of acetylcholine receptors.

Acetylcholinesterase↗
PubMed1990

The histochemical localization of ATPase, cholinesterase and acid phosphatase activity in Culex pipiens (Diptera, Culicidae) larvae using a methacrylate embedding technique.

A method is described for the demonstration of ATPase, Cholinesterase and acid phosphatase activity in thin sections of mosquito larvae fixed in 1:9 v/v mixture of acetone and 10% neutral buffered formalin and embedded in hydroxyethyl methacrylate (HEMA). ATPase activity, observed as a black brown precipitate, was found in the brush border of gastric caeca and microvilli of columnar epithelial cells of the hind gut and Malpighian tubules. Some basal cell membrane activity could also be seen. Cholinesterase activity was found in thoracic and abdominal ganglia. The reaction product had a fine particulate appearance and predominated in the axonal processes. Azo dye reaction product indicative of acid phosphatase activity was found in the epithelial cells of the midgut and gastric caeca. Lysosomal and extra-lysosomal activity was observed, the larger secondary lysosomal sources predominating in the perinuclear region. The fixation regime and embedding procedure outlined has enabled a sub-cellular localization of enzymatic activities which is superior to that obtainable with conventional procedures.

Acid Phosphatase↗
PubMed1993

Regulation of central muscarinic receptors after cholinesterase inhibition: effect of clonidine.

In rats, the injection of soman (70 micrograms/kg, SC) resulted in a 90% inhibition of the cholinesterase (ChE) activities in three brain regions. The density (Bmax) for muscarinic acetylcholine receptors (mAChRs) following a single injection of soman was significantly reduced at 2 h after injection in the cortex and hindbrain. Bmax values, however, returned to baseline within 24 h. Subacute (repeated injection every 15 min) treatment with a sublethal dose of soman over 2 h also decreased the density of mAChRs. In both cases the density of mAChRs was reduced by about 15% for the cortex and 17% for the hindbrain (the midbrain was also reduced by 18% for subacute injections). Chronic administration (once daily for 7 days) of soman (20 micrograms/kg, SC) produced maximal inhibition of ChE activity but did not significantly downregulate mAChRs. Clonidine pretreatment reversed the soman-induced mAChR downregulation in cortex and hindbrain produced by acute soman administration. Thus, marked reduction in the levels of brain ChE is not the only factor involved in the production of mAChR downregulation to cholinesterase inhibitors.

Animals↗
PubMed1987

Quantitative monitoring by high-performance liquid chromatography of the dissociation of human serum cholinesterase by limited proteolysis.

Proteolytic action on human serum cholinesterase, a tetrameric enzyme, results in a partial disintegration which can be recorded only qualitatively by time-consuming electrophoretic techniques. In this study, a rapid high-performance liquid chromatographic method was used for the separation and determination of the active dissociation products. Separation of the cholinesterase subunits was accomplished by high-performance gel permeation chromatography on a combination of DIOL columns (Zorbax GF 450/GF 250) in 0.2 M phosphate buffer (pH 7.0). Detection and quantification of enzyme activity in the fractionated eluate were carried out using a Flexigem analyser (substrate, butyrylthiocholine). On limited tryptic digestion of partially purified human ChE, up to three peaks of enzyme activity could be identified. Their elution volumes corresponded to apparent molecular masses of 480,000, 270,000 and 120,000, indicating, in addition to the tetrameric holoenzyme, a dimeric and a monomeric form. Quantification of the relative amounts of individual enzyme activity peaks revealed that in the course of degradation, the dimer appeared first, followed by the monomer. This suggests that the first step in the sequence of dissociation is cleavage of the tetramer into a pair of dimers, then further into the monomeric subunit. During the incubation with trypsin, a significant change in the pattern of the different peaks had already occurred when the total enzyme activity was only slightly reduced.

Cholinesterases↗