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)

We postulate that the effect of cholinesterase inhibitors to ameliorate the cholinergic deficit in Alzheimer's disease is related to their ability to maintain long-lasting, non-toxic steady-state levels of acetylcholine in cortex. We investigated the effect of the cholinesterase inhibitor, MDL 73,745 (2,2,2-trifluoro-1-(3-trimethylsilylphenyl)ethanone), on the extracellular levels of acetylcholine, norepinephrine, dopamine and 5-hydroxytryptamine in the cerebral cortex of the rat by high-performance liquid chromatography coupled with electrochemical detection. The drug significantly increased acetylcholine levels above the baseline at 2 and 10 mg/kg s.c., but not at the 1 mg/kg dose. At both 2 and 10 mg/kg there was a good correlation between cholinesterase inhibition and acetylcholine increase in cortex. At the 2 and 10 mg/kg doses, the maximal cholinesterase inhibition was 64% and 77%, respectively, and the increase in acetylcholine release was 481% and 1016%, respectively. Norepinephrine and dopamine, but not 5-hydroxytryptamine levels, were also significantly increased by the 10 mg/kg dose. The increases of norepinephrine and dopamine levels reached a maximum of 124% and 370%, respectively, and continued for a period of at least 8 h. Cholinergic side-effects were most marked at the 10 mg/kg dose but were also noticeable at the 2 mg/kg dose in the form of fasciculations, tremor and splay.
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PMID:Effect of MDL 73,745 on acetylcholine and biogenic amine levels in rat cortex. 778 1

A microdialysis technique was used to investigate the effect of physostigmine (PHY) and heptylphysostigmine (HEP), administered systemically or locally, on the extracellular levels of acetyl-choline (ACh), norepinephrine, dopamine and 5-hydroxytryptamine in the cerebral cortex of the rat. Levels of these neurotransmitters in dialysates were assayed simultaneously with two different high pressure liquid chromatography systems. No cholinesterase inhibitor was added into the probe to increase detection of ACh after systemic administration. Cholinesterase inhibition and its relation to ACh levels were also studied. Systemic administration of two doses of cholinesterase inhibitor [PHY (30 and 300 micrograms/kg) and HEP (2 and 5 mg/kg)] produced a dose-dependent increase in ACh levels. Local perfusion of these drugs through the probe elicited a strong increase in extracellular ACh. HEP produced a longer lasting inhibition of cholinesterase and a more prolonged elevation of ACh in cerebral cortex than PHY. After systemic administration of PHY (both doses), we observed a significant increase of norepinephrine levels. This effect was weaker after HEP. Local administration through the probe did not modify norepinephrine concentration. Dopamine levels were also increased after systemic administration. ONly HEP perfused into the probe elicited a significant increase in extracellular dopamine. Systemic or local administration did not modify 5-hydroxytryptamine levels. These observations suggest a more favorable pharmacological profile for HEP as a potential drug for Alzheimer disease, as compared to PHY.
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PMID:Cholinesterase inhibitor effects on neurotransmitters in rat cortex in vivo. 791 96

1. The synthetic cationic polypeptide, poly-L-arginine (0.03-1 mg ml-1) induced concentration-dependent contraction of guinea-pig and rat isolated trachea. In guinea-pig isolated trachea, this response was attenuated in the presence of the muscarinic cholinoceptor antagonist, atropine (0.1 microM) and augmented by the acetylcholinesterase inhibitor, ecothiophate (0.1 microM). The neuronal sodium channel blocker, tetrodotoxin (3 microM) failed to alter the contractile response to poly-L-arginine and acetylcholine. 2. The contractile response to poly-L-arginine in rat isolated trachea was inhibited in the presence of atropine (0.1 microM) and the 5-hydroxytryptamine (5-HT) receptor antagonist, methysergide (1 microM). Treatment of rat tracheal preparations with capsaicin (100 microM) or tetrodotoxin (3 microM) failed to alter the contractile response to poly-L-arginine. In contrast, ecothiophate (0.1 microM) augmented the contractile response to poly-L-arginine in rat isolated trachea. 3. Electrical field stimulation (5 Hz, 2 min) of epithelium-denuded guinea-pig tracheal preparations preloaded with [3H]-choline resulted in a contractile response and the simultaneous efflux of radioactivity into the superfusate. Both these responses were abolished in the presence of tetrodotoxin (1.5 microM). Poly-L-arginine (1 mg ml-1) also increased the efflux of total radioactivity from epithelium-denuded guinea-pig isolated tracheal preparations preloaded with [3H]-choline, but this response was tetrodotoxin-insensitive. The negatively charged polyanion, heparin (1 mg ml-1) failed to increase significantly the efflux of radioactivity from epithelium-denuded preparations. 4.In conclusion, the synthetic cationic polypeptide, poly-L-arginine, caused contraction of guinea-pig isolated tracheal preparations via the release of acetylcholine from parasympathetic nerves. Similarly,poly-L-arginine-induced contraction of rat isolated trachea is secondary to the release of acetylcholine from parasympathetic nerves and/or the release of mast cell-derived 5-HT.
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PMID:Poly-L-arginine-mediated release of acetylcholine from parasympathetic nerves in rat and guinea-pig airways. 792 18

Oral administration of the insecticide endosulfan (2 mg/kg per day) for 90 days in immature male rats resulted in an inhibition of pole-climbing escape response to electric shock (unconditioned) and avoidance response to buzzer (conditioned). These responses reflect respectively their learning and memory processes. The escape response but not the avoidance response was reinstated significantly by the 5-hydroxytryptamine (5-HT) depletor, p-chlorophenylalanine (PCPA, 100 mg/kg per day for 3 days). Endosulfan increased 5-HT concentrations in the cerebrum and midbrain regions. Protein content and acetylcholinesterase activity were unaltered in the brain. The spontaneous motor activity of these animals was stimulated. Their muscle coordination on rota-rod apparatus was unaffected. These findings were interpreted as an indication that a motivation deficit and not motor impairment was responsible for the inhibitory action of endosulfan on pole-climbing escape and avoidance responses. Thus, endosulfan was suggested to produce learning and memory deficit. A serotonergic involvement was significant in endosulfan-induced learning impairment and it appeared to be negligible in its memory disrupting action.
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PMID:The neurobehavioural toxicity of endosulfan in rats: a serotonergic involvement in learning impairment. 815 75

The present study has been undertaken in order to investigate whether aging is accompanied by alterations in the thymic autonomic innervation. The results showed that in aged rats compared to young adult rats the density of monoaminergic histofluorescent nerve profiles decreased remarkably, while their pattern of intrathymic distribution remained unchanged. The thymic concentrations of noradrenaline (NA) and dopamine (DA) also significantly decreased between the age of 12 and 18 months. However, the density of thymic autofluorescent cells (afc) markedly increased over the same period, as well as the concentration of 5-hydroxytryptamine (5-HT). The aged rat thymus seemed to be able to maintain its cholinergic innervation in terms of density and pattern of distribution, while the density of cells with intracytoplasmic acetylcholinesterase (AChE) staining even increased. The neurochemical measurement showed an increase in the activity of AChE between the age of 9 to 18 months. The results indicate an altered relation between the components of thymic autonomic innervation of aged rats that might be related to the reduced immunocompetence of their T cells.
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PMID:Relationships between monoaminergic and cholinergic innervation of the rat thymus during aging. 829 58

The central (CNS) and peripheral (PNS) nervous systems of the cyclophyllidean tapeworm, Moniezia expansa, were examined for the presence of cholinergic, serotoninergic and peptidergic elements using enzyme cytochemical and immunocytochemical techniques in conjunction with light and confocal scanning laser microscopy. Cholinesterase activity and 5-hydroxytryptamine- and regulatory peptide-immunoreactivities (IRs) were localized to the nerve fibres and cell bodies of all of the major neuronal components in the CNS of the worm, including the cerebral ganglia and connecting commissure, the 10 longitudinal nerve cords and associated transverse ring commissures. Although each of the 3 systems appeared well developed and comprised a significant portion of the nervous system, the serotoninergic constituent was the most highly developed, consisting of a vast array of nerve fibres and cell bodies distributed throughout the strobila of the worm. A close association of cholinesterase reactivity and peptide-IRs was evident throughout the CNS, indicating the possible co-localization of acetylcholine and neuropeptides. Within the PNS, cholinergic activity and serotoninergic- and peptidergic-IRs occurred in the subtegumental network of nerve fibres and somatic musculature. Although all 3 neurochemical elements were present in the acetabula, they were found in different nerve fibres; only cholinergic and peptidergic cell bodies were found. The common genital opening, vagina and ootype regions of the reproductive system displayed a rich innervation of all 3 types of neuronal populations. Within the peptidergic system, immunostaining with antisera raised to the C-terminus of the neuropeptide Y superfamily of peptides and the invertebrate peptides, neuropeptide F (M. expansa) and FMRFamide was the most prevalent. Limited positive-IR for substance P and neurokinin A were also recorded in the CNS of the worm.
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PMID:The cholinergic, serotoninergic and peptidergic components of the nervous system of Moniezia expansa (Cestoda, Cyclophyllidea). 831 39

Rats fed with choline-deficient diets are known as a model of aging and learning impairments due to acetylcholine (ACh) deficiency in the brain which may be associated with a decrease in acetylcholinesterase (AChE; EC 3.1.1.7). To determine the role of AChE in bronchial responsiveness, we examined the contractile response of isolated lung parenchymal strips to ACh in control rats and rats fed with choline-deficient diets. Concentration-response curves to ACh shifted to the lower concentrations and the maximum response to ACh was greater in rats fed with choline-deficient diets than in control rats (P < 0.01). Physostigmine (10(-6) M) mimicked effects of choline-deficient diets on the contractile response to ACh. However, concentration response curves to carbachol and 5-hydroxytryptamine did not differ between control rats and rats fed with choline-deficient diets. Choline-deficient diets significantly decreased the AChE activity from homogenates of lung parenchymal tissues (P < 0.01). These results suggest that a decrease in AChE activity of lung tissues may relate to airway hyperresponsiveness to ACh.
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PMID:Peripheral airway hyperresponsiveness in the choline-deficiently fed rat. 832 93

E2020 is a piperidine cholinesterase inhibitor (ChEI) which is structurally distinct from other compounds presently under study for treatment of Alzheimer's disease. We studied the effect of this compound on acetylcholine (ACh), norepinephrine (NE), dopamine (DA) and serotonin (5-HT; 5-hydroxytryptamine) by means of transcortical microdialysis in the cortex of awake rats with no ChEI in the probe. We also compared the inhibition of brain cholinesterase (ChE) by two different approaches. Following 0.5 and 2.0 mg/kg s.c. administration, the increase in ACh was 200% (30 min) and 2100% (1 hr), respectively. The maximal ChE inhibition at 30 min was 35.5% (2.0 mg/kg) and 15.6% (0.5 mg/kg) when measured as ACh hydrolysis in the diluted homogenate. After the 2.0 mg/kg dose, phosphorylation by DFP was completely blocked at 30 min. After 0.5 mg/kg, ChE phosphorylation was maximally inhibited at 30 min (56%) and declined thereafter to negligible levels by 3 hr. In addition, E2020 increased extracellular levels of catecholamines in cortex in agreement with our previous findings with carbamate ChEI. Following 2.0 mg/kg, both NE (100%) and DA (80%) were elevated, whereas after 0.5 mg/kg only NE (50%) was affected. Neither dose affected extracellular 5-HT. Thus, E2020, which inhibits brain ChE by a novel, reversible mechanism, elevates extracellular ACh in a comparable manner to other centrally-active ChEI, and this elevation of ACh is associated with stimulation of catecholamine release.
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PMID:The effect of the selective reversible acetylcholinesterase inhibitor E2020 on extracellular acetylcholine and biogenic amine levels in rat cortex. 873 90

The purpose of this study was to assess the compatibility, in terms of red blood cell acetylcholinesterase (AChE) inhibition, of ondansetron (OND; a 5-hydroxytryptamine subtype-3 receptor antagonist) with the organophosphorus pretreatment compound pyridostigmine (PYR) after simultaneous oral (p.o.) administration to guinea pigs. The time-course of PYR-induced (0.94 mg/kg, p.o.) AChE inhibition was determined in the absence and presence of OND. Ondansetron (10, 20 and 30 mg/kg; p.o.) did not modify AChE inhibition, whereas concurrent administration of PYR with OND (10 or 20 mg/kg; p.o.) produced significantly greater decreases in AChE activity than PYR alone. The decreases in AChE activity for PYR plus OND, 10 and 20 mg/kg, (between 30 -240 min) were 12.3 +/- 2.8% and 16.1 +/- 2.3% (mean +/- SD) respectively relative to PYR alone. The slope for recovery of AChE activity (120 - 240 min) was 0.0914 for PYR alone; recovery rates (slopes) for PYR plus OND, 10 and 20 mg/kg, were 0.0796 and 0.0433 respectively. Additionally, altered PYR-induced AChE activity profiles were ameliorated when PYR and OND (20 mg/kg) were administered 150 min apart. Since the results of this study provided evidence that the oral administration of OND alone did not inhibit AChE, the changes in PYR-induced AChE activity by the simultaneous administration of OND suggest mechanisms other than a direct action on the enzyme. The significance of these findings is that the increased AChE inhibition resulting from simultaneous oral administration of both component could result in undesirable cholinergic toxicities and subsequent perform decrements.
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PMID:The effect of ondansetron on pyridostigmine-induced blood acetylcholinesterase inhibition in the guinea pig. 880 50

Previous studies in our laboratory and others suggested that activation of 5-HT2 receptors mediates 5-hydroxytryptamine (5-HT)-induced contraction of airway smooth muscle and that this response is dependent in part on endogenous acetylcholine (ACh). The purpose of the present study was to confirm a role for 5-HT2 receptors and endogenous ACh in 5-HT-induced contraction of rat bronchi. In this study, we examined the effects of 5-HT2 receptor antagonists (ketanserin and LY53857), acetylcholinesterase inhibitors (physostigmine and neostigmine), and a muscarinic receptor alkylating agent [propylbenzilylcholine mustard (PBCM)] on contractile responses evoked by 5-HT and the 5-HT2 receptor agonist, alpha-methyl-5-hydroxytryptamine (alpha-Me-5-HT). Concentration-response curves generated in isolated rat intrapulmonary bronchi in response to 5-HT and alpha-Me-5-HT were superimposable. Inhibition of acetylcholinesterase by physostigmine or neostigmine potentiated contractile responses elicited by 5-HT and alpha-Me-5-HT. Alkylation of muscarinic receptors with PBCM decreased maximal responses elicited by 5-HT or alpha-Me-5-HT in a concentration-dependent manner. Maximum contraction attained with exogenous ACh was decreased by PBCM in a concentration-dependent manner and, at the highest concentration evaluated, ACh-induced contractions were abolished. 5-Hydroxytryptamine-induced contraction was inhibited competitively by low concentrations of the 5-HT2-receptor selective antagonist, ketanserin; higher concentrations abolished contractile responses to the amine. The inhibition of 5-HT-induced contractile responses by another 5-HT2-receptor selective antagonist, LY53857, was non-competitive in nature. Together, the results suggest that 5-HT contracts rat airways directly by activating 5-HT2 receptors located on airway smooth muscle and indirectly by activation of 5-HT2 receptors on parasympathetic nerve endings to cause release of ACh. The potential physiological implication of these findings is that 5-HT released in inflammatory conditions such as asthma may play a role in causing bronchoconstriction by releasing ACh or by augmenting release of ACh from activated cholinergic nerves.
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PMID:Mechanisms of 5-hydroxytryptamine-induced contraction of isolated rat intrapulmonary bronchi. 881 82


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