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

---

Query: EC:3.1.1.7 (acetylcholinesterase)
28,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

9-Amino-1,2,3,4-tetrahydroacridine (THA), an inhibitor of acetylcholinesterase, has been proposed as a treatment for Alzheimer's disease on the basis of its ability to increase cerebral levels of acetylcholine. THA shares structural features with aminoquinoline compounds known to be inhibitors of histamine-N-methyltransferase (HNMT). THA was found to be a potent competitive inhibitor of rat brain HNMT in vitro, with a Ki of 35 nM with respect to both histamine and S-adenosyl-L-methionine, the co-substrate. Two hours after systemic administration of THA (5 and 10 mg/kg, i.p.), HNMT from rat brain was largely inhibited. The levels of histamine in striatum and cerebral cortex were elevated by this treatment. Thus, THA at moderate doses is able to alter histamine metabolism in the central nervous system.
...
PMID:Inhibition of rat brain histamine-N-methyltransferase by 9-amino-1,2,3,4-tetrahydroacridine (THA). 240 87

The adrenal gland of the rat was analysed with immunohistochemistry and antisera to neuropeptide tyrosine, to the catecholamine-synthesizing enzymes tyrosine hydroxylase, phenyl-ethanolamine-N-methyltransferase, and to acetylcholinesterase and with in situ hybridization using a nick-translated 280 base pair deoxyribonucleic acid probe coding for exon 2 of the rat neuropeptide tyrosine gene. Neuropeptide tyrosine-like immunoreactivity was observed in three structures: chromaffin cells, medullary ganglion cells and nerve fibers. The chromaffin cells were of both the noradrenaline- and adrenaline-type. The ganglion cells did not seem to contain any catecholamine-synthesizing enzymes but exhibited a strong immunoreaction for acetylcholinesterase. They were thus in all probability cholinergic neurons. In situ hybridization using the nick-translated deoxyribonucleic acid probe to rat neuropeptide tyrosine messenger ribonucleic acid revealed a very high-grain density over the ganglion cells, a moderate density over the chromaffin cells and a low background over cortex, in agreement with the immuno-histochemical demonstration of neuropeptide tyrosine-like immunoreactivity both in chromaffin and ganglion cells. The intense neuropeptide tyrosine-like immunoreactivity and low content of neuropeptide tyrosine messenger ribonucleic acid suggest that the chromaffin cells have fairly large peptide stores but that the peptide turnover is low. In contrast, the ganglion cell bodies seem to contain low amounts of neuropeptide tyrosine-like immunoreactivity but exhibit a high neuropeptide tyrosine synthesis rate. Preliminary studies with the amine-depleting drug reserpine revealed an increase in messenger ribonucleic acid both in ganglion cells and medullary cells. In the chromaffin cells the highest activity was seen 3 and 4 days after injection, and the levels were down to normal after 8 days. The present findings demonstrate neuropeptide tyrosine synthesis and storage in two cell populations in the adrenal medulla. In situ hybridization with its cellular resolution can provide information on possible differential effects of drugs and experimental procedures on these two neuropeptide tyrosine stores.
...
PMID:Neuropeptide tyrosine in the rat adrenal gland--immunohistochemical and in situ hybridization studies. 289 91

A rat brain P3 fraction enriched in ER derived microsomes was centrifuged through a 20-40% linear sucrose gradient in a Beckman Ti-14 Zonal rotor and 11 fractions were obtained. The distribution of marker enzyme activities and protein were determined in these 11 subfractions. NADPH-Cytochrome C reductase, choline phosphotransferase were employed for endoplasmic reticulum, Na+,K+-ATPase, 5'-nucleotidase, and acetylcholinesterase were employed for plasma membrane, 2',3'-cyclic nucleotide phosphohydrolase was employed for myelin. The bulk of the protein was recovered in the 24-34% sucrose fractions, Na+,K+-ATPase, 5'-nucleotidase, and acetylcholinesterase were in the 22-38% sucrose fractions while NADPH-cytochrome C reductase and CNPase were enriched in the 20-22% sucrose fractions. The ethanolamine and the serine base exchange activities had a bimodal distribution, with highest specific activities in sucrose fractions 32-34% and 20-24%. Choline base exchange activity was nearly undetectable in all the fractions. The specific activities of CDP-choline phosphotransferase, and phospholipid-N-methyltransferase were highest in the 20-22% sucrose fraction. Phospholipid-N-methyltransferase activity was significantly stimulated in the presence of exogenous phospholipid acceptors as phosphatidylethanolamine or phosphatidylmonomethylethanolamine or phosphatidyldimethylethanolamine, however, the greatest response was with phosphatidylmonomethylethanolamine. The rat brain P3 fraction yielded a population of a membrane at the light end of the sucrose gradient which has a buoyant density similar to myelin but seemed to be enriched with NADPH cytochrome C reductase and phospholipid modifying enzymes. This is in contrast to liver microsomes submitted to a similar fractionation.
...
PMID:Distribution of selected phospholipid modifying enzymes in rat brain microsomal subfractions prepared by density gradient zonal rotor centrifugation. 298 22

In the rat, systemic administration of murine monoclonal antibodies against acetylcholinesterase caused rapid piloerection and ptosis (within 30-60 min after the injection). Using indirect immunohistochemistry the effect of these antibodies on peptides and enzyme expression was studied in the rat adrenal gland. Four days after antibody administration a total disappearance of acetylcholinesterase-immunoreactive fibers was observed. However, groups of acetylcholinesterase-immunoreactive chromaffin cells and intramedullary ganglion cells, both cell types showing acetylcholinesterase immunoreactivity also in the control adrenal medulla, expressed increased immunoreactivity. Analysis revealed that the acetylcholinesterase-immunoreactive chromaffin cell groups lacked phenylethanolamine-N-methyltransferase staining both in controls and treated rats. Antibody administration also affected levels of several peptides present in nerve fibers and chromaffin cells. Thus, the number of cells expressing enkephalin, calcitonin gene-related peptide and galanin was dramatically increased compared to the very few cells observed containing these three peptides in the normal gland. The majority of cells expressing enkephalin after antibody treatment also showed phenylethanolamine-N-methyltransferase immunoreactivity. In contrast, the few chromaffin cells expressing strong enkephalin-like immunoreactivity in controls were phenylethanolamine-N-methyltransferase negative. The sparse networks of calcitonin gene-related peptide- and galanin-positive fibers found in control adrenals were unchanged after the antibody treatment. However, the dense network of enkephalin varicose fibers totally disappeared after the antibody injection. A few substance P- and somatostatin-immunoreactive cells, not present in the normal gland, appeared after administration of the antibodies, whereas no changes were encountered with regard to immunoreactive nerve fibers. No clear differences between normal and treated animals could be observed in chromaffin cells with regard to immunoreactivity for neuropeptide Y or any of the four catecholamine-synthesizing enzymes, tyrosine hydroxylase, aromatic 1-amino acid decarboxylase, dopamine beta-hydroxylase or phenylethanolamine-N-methyltransferase. The present findings demonstrating a disappearance of acetylcholinesterase- and enkephalin-immunoreactive nerve fibers in the adrenal gland after intravenous injection of acetylcholinesterase antibodies support earlier reports showing that these antibodies cause degeneration of preganglionic fibers, and that neuronal decentralization of the adrenal gland induces marked increases in the levels of several peptides in chromaffin cells.
...
PMID:Effects of antibodies against acetylcholinesterase on the expression of peptides and catecholamine synthesizing enzymes in the rat adrenal gland. 810 82

The development of neuron-like cholinergic immunophenotypes by adrenal chromaffin cells was studied in 10-week-old mouse adrenal medullary grafts. Fragments of chromaffin tissue were implanted into mouse hippocampus, and antibodies specific for neurofilaments (NF), neuron-specific enolase (NSE), choline acetyltransferase (ChAT), acetylcholinesterase (AChE), and phenylethanolamine-N-methyltransferase (PNMT) were applied to the grafts. Adrenal medulla grafts survived well and most of the transplanted cells were either round or polygonal. A minority of chromaffin cells elaborated an intermediate or sympathetic neuron phenotype. Chromaffin cells showed pronounced immunoreactivity for NSE in their perikarya and axon-like processes: immunoreactivity for NF was only found in a few processes. In adjacent immunohistochemically stained sections, the transplanted cells stained for ChAT and AChE. At the electron-microscope level, the immunohistochemical reactions for the two acetylcholine-related enzymes were mainly located on the endoplasmic reticulum and in cell processes. Immunoreactivity for PNMT was found to decline in transplanted chromaffin cells below that of normal adrenal medulla. These observations suggest that, in adrenal medullary grafts implanted into the hippocampus, chromaffin cells are endowed with neuron-like cholinergic immunophenotypes.
...
PMID:Mouse adrenal chromaffin cells can transform to neuron-like cholinergic phenotypes after being grafted into the brain. 824 6

Cognitive impairment in schizophrenia occurs in the early phases of the disease and remains throughout its course. The basis for cognition lies in two main brain regions: the prefrontal cortex and hippocampus. Positron emission tomography, functional magnetic resonance imaging, and proton magnetic spectroscopy studies have shown that prefrontal cortex and hippocampus activity and cell density are lower in patients with schizophrenia than in healthy controls. Dopamine remains the fundamental neurotransmitter involved with schizophrenia. Catechol- O -methyltransferase accounts for about 60% of dopamine metabolism in the prefrontal cortex. Functional polymorphism for the catechol- O -methyltransferase genotypes has been identified in patients with schizophrenia. Those with the valine-valine genotype demonstrate rapid inactivation of dopamine, and performance in cognitive testing in patients is poorer with this allele than with other genotypes. N -methyl-D-aspartate and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate acid receptors are also strongly associated with cognitive impairment. Changes occur in apolipoproteins D and E, cholinesterase enzyme activity, neurotensin, and neural growth factors, leading to a possible neurodegenerative process and cognitive impairment in patients with schizophrenia. A fundamental link between psychosis and neurocognition probably arises from complex interactions between these systems at the intracellular secondary messenger system and with protein phosphorylation. Atypical antipsychotics evaluated in receptor models, cell cultures, and animal behavior paradigms indicate that these agents may provide neuroprotective effects. Clinical studies with atypical antipsychotics have consistently demonstrated improvement in cognitive symptoms, and such improvement appears to be correlated with improvement of negative symptoms. A neurodevelopmental model of cognitive impairment in schizophrenia aids in understanding why atypical antipsychotics improve cognitive symptoms.
...
PMID:Implications for atypical antipsychotics in the treatment of schizophrenia: neurocognition effects and a neuroprotective hypothesis. 1558 43

Novel highly affine histamine H3 receptor ligands with additional inhibitory effects on the main histamine metabolizing enzyme in the brain, N-methyltransferase, chemically show structural elements of the acetylcholinesterase inhibitor tacrine. H3 receptor antagonism, inhibition of metabolisation of neuronal histamine as well as inhibition of hydrolysis of acetylcholine are each one believed to improve reduced cognitive functions, which is useful for symptomatic treatment of Alzheimer's disease. Some of the new compounds proved in a slightly modified colorimetric Ellmann's assay to be potent inhibitors of acetylcholinesterase and of butyrylcholinesterase which is another catalytic enzyme hydrolysing acetylcholine. Some compounds with (sub)nanomolar activities on the histamine-related targets are also active in the nanomolar concentration range on both cholinesterase targets being 5- to 40-times more potent than tacrine. Preliminary structure-activity relationships could already be drawn from the small number of compounds. The compounds acting as hybrid drugs simultaneously on four different targets to enhance cognitive functions via different pathways are promising lead structures for a new approach in the treatment of Alzheimer's disease.
...
PMID:Multiple enzyme inhibitions by histamine H3 receptor antagonists as potential procognitive agents. 1659 55

Alzheimer's disease (AD) is a progressive neurodegenerative disorder of the central nervous system (CNS) which is the most common cause of dementia in the elderly. It is characterized by the deficits in the cholinergic system and presence of characteristic hallmarks: neurofibrillary tangles and amyloid plaques. Since the cholinergic system plays an important role in the regulation of learning and memory processes it became a target for the design of anti-alzheimer drugs. Cholinesterase inhibitors enhance cholinergic transmission indirectly, by inhibiting the enzyme which hydrolyses acetylcholine. It has been also demonstrated that acetylcholinesterase (AChE) is involved in the development of amyloid plaques. Therefore, substances which are AChE inhibitors (AChEI) are the only drugs approved for the symptomatic treatment of AD. This review presents the main classes of cholinesterase inhibitors developed recently for the treatment of AD. We have started with the analogues of the existing drugs: tacrine, donepezil, rivastigmine and galantamine which are still of interest for many research groups. Among them there is a very interesting group--dual binding site inhibitors characterized by increased inhibitory potency against AChE and amyloid plaques formation. There is also a group of compounds with additional properties such as: antioxidant activity, affinity to 5-HT(3) receptors, inhibition of N-methyltransferase that metabolize histamine, which can be beneficial for the treatment of AD. Furthermore there are some interesting compounds which belong to different chemical groups also of natural origin. In this review we sum up current research concerned with development of AChEIs which can be more effective in the future treatment of AD.
...
PMID:Recent developments in cholinesterases inhibitors for Alzheimer's disease treatment. 1797 17

Guanidinoacetate methyltransferase (GAMT) deficiency is a disorder of creatine metabolism characterized by low plasma creatine concentrations in combination with elevated guanidinoacetate (GAA) concentrations. The aim of this work was to investigate the in vitro effect of guanidinoacetate in NTPDase, 5'-nucleotidase and acetylcholinesterase activities in the synaptosomes, platelets and blood of rats. The results showed that in synaptosomes the NTPDase and 5'-nucleotidase activities were inhibited significantly in the presence of GAA at concentrations of 50, 100, 150 and 200 microM (P < 0.05). However, in platelets GAA at the same concentrations caused a significant increase in the activities of these two enzymes (P < 0.05). In relation to the acetylcholinesterase activity, GAA caused a significant inhibition in the activity of this enzyme in blood at concentrations of 150 and 200 microM (P < 0.05), but did not alter the acetylcholinesterase activity in synaptosomes from the cerebral cortex. Our results suggest that alterations caused by GAA in the activities of these enzymes may contribute to the understanding of the neurological dysfunction of GAMT-deficient patients.
...
PMID:Effects in vitro of guanidinoacetate on adenine nucleotide hydrolysis and acetylcholinesterase activity in tissues from adult rats. 1825 32

Persistent psychotic symptoms will develop in up to 60% of patients with Parkinson disease (PD). The initial approach to the management of PD psychosis (PDP) begins with addressing concurrent systemic conditions associated with psychotic behavior, such as delirium, medical conditions (eg, infections), psychiatric disorders (eg, major depression with psychotic symptoms, mania, schizophrenia), and substance misuse or withdrawal. A review of current medications is recommended, and medications that may trigger psychotic symptoms should be eliminated. If possible, antiparkinson medications should be reduced to the minimum therapeutic dose or discontinued in a sequential manner. Generally, dose reduction or discontinuation of anticholinergics is attempted first, followed by that of monoamine oxidase B inhibitors, amantadine, dopamine agonists, catechol-O-methyltransferase inhibitors, and lastly carbidopa/levodopa. The aim of antiparkinson medication dose reduction is to achieve a balance between improving drug-related psychotic symptoms and not significantly worsening the motor symptoms of PD. If additional measures are needed for chronic PDP treatment, the use of second-generation antipsychotics, such as clozapine, pimavanserin, or quetiapine, must be considered. The first-generation antipsychotics (eg, fluphenazine, haloperidol) are not recommended. In the patient with comorbid dementia, the addition of a cholinesterase inhibitor might also be beneficial for PDP. The choice of agent is based on patient-specific parameters, potential benefit, and side effects.
...
PMID:Treatment of psychotic symptoms in patients with Parkinson disease. 2995 32


1

---