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

The phenomenon of dissociated memory retrieval is observed when some influences (for example, pharmacological) on the brain result in specific changes of long-term memory. The purpose of present paper is to reveal possibilities of the phenomenon for study of long-term memory retrieval. Pharmacologically-induced dissociated states could be identified when the retrieval of responses learned before treatment is temporarily blocked by the drug influence, but the ability of the animals to learn new tasks is intact. Furthermore, memory traces that were formed in drugged state are not accessible for the retrieval in normal state and only the same drug treatment allows retrieving them. In the present work, dissociated learning of food-motivated tasks was carried out in Wistar rats with cholinesterase inhibitor physostigmine (0.5 mg/kg, intraperitonealy) or general anaesthetic sodium pentobarbital (15 mg/kg, intraperitonealy.). The retrieval of dissociated responses was studied under the influence of various doses of the same drugs. The results revealed the asymmetry of memory dissociation with physostigmine in contrast to pentobarbital-induced memory dissociation. Gradual access for the retrieval of dissociated memory traces after pharmacological modulation of cholinergic and GABA-ergic brain systems was shown. It was suggested an important role of hippocampus in memory dissociation, as a structure-performing match-mismatch operations between different retrieved memory traces.
...
PMID:Memory dissociation: the approach to the study of retrieval processes. 1059 20

One of the most prominent cholinergic deficit in Alzheimer's disease (AD) is the reduced number of nicotinic acetylcholine receptors (nAChR) in the hippocampus and cortex of AD patients, as compared to age-matched controls. This deficit results in reduced nicotinic cholinergic excitation which may not only impair postsynaptic depolarization but also presynaptic neurotransmitter release and Ca2+-dependent intracellular signaling, including transcriptional activity. Presently, the most common approach to correct the nicotinic cholinergic deficit in AD is the application of cholinesterase inhibitors. Due to the resulting increase in synaptic acetylcholine levels, both in concentration and time, additional nAChR molecules, e.g. those more distant from the ACh release sites, could be activated. As an obvious disadvantage, this approach affects cholinergic neurotransmission as a whole, including muscarinic neurotransmission. As a novel and alternative approach, a treatment strategy which exclusively targets nicotinic receptors is suggested. The strategy is based on a group of modulating ligands of nicotinic receptors, named allosterically potentiating ligands (APL), which increase the probability of channel opening induced by ACh and nicotinic agonists, and in addition decrease receptor desensitization. The action of APL on nicotinic receptors is reminiscent of that of benzodiazepines on GABA(A) receptors and of that of glycine on the NMDA-subtype of glutamate receptor. Representative nicotinic APL are the plant alkaloids physostigmine, galanthamine and codeine, and the neurotransmitter serotonin (5HT). The potentiating effect of APL on nicotinic neurotransmission has been shown by whole-cell patch-clamp studies in natural murine and human neurons, and in murine and human cell lines expressing various subtypes of neuronal nAChR.
...
PMID:Allosterically potentiating ligands of nicotinic receptors as a treatment strategy for Alzheimer's disease. 1094 46

Chlorpyrifos targets mammalian brain development through a combination of effects directed at cholinergic receptors and intracellular signaling cascades that are involved in cell differentiation. We used sea urchin embryos as an invertebrate model system to explore the cellular mechanisms underlying the actions of chlorpyrifos and to delineate the critical period of developmental vulnerability. Sea urchin embryos and larvae were exposed to chlorpyrifos at different stages of development ranging from early cell cleavages through the prism stage. Although early cleavages were unaffected even at high chlorpyrifos concentrations, micromolar concentrations added at the mid-blastula stage evoked a prominent change in cell phenotype and overall larval structure, with appearance of pigmented cells followed by their accumulation in an extralarval cap that was extruded from the animal pole. At higher concentrations (20-40 microM), these abnormal cells constituted over 90% of the total cell number. Studies with cholinergic receptor blocking agents and protein kinase C inhibitors indicated two distinct types of effects, one mediated through stimulation of nicotinic cholinergic receptors and the other targeting intracellular signaling. The effects of chlorpyrifos were not mimicked by chlorpyrifos oxon, the active metabolite that inhibits cholinesterase, nor by nonorganophosphate cholinesterase inhibitors. Dieldrin, an organochlorine that targets GABA(A )receptors, was similarly ineffective. The effects of chlorpyrifos and its underlying cholinergic and signaling-related mechanisms parallel prior findings in mammalian embryonic central nervous system. Invertebrate test systems may thus provide both a screening procedure for potential neuroteratogenesis by organophosphate-related compounds, as well as a system with which to uncover novel mechanisms underlying developmental vulnerability.
...
PMID:An invertebrate model of the developmental neurotoxicity of insecticides: effects of chlorpyrifos and dieldrin in sea urchin embryos and larvae. 1148 62

1. The whole-cell configuration of the patch-clamp technique was used to study the modulation of giant depolarizing potentials (GDPs) by nicotinic acetylcholine receptors (nAChRs) in CA3 hippocampal neurons in slices from postnatal day (P) 2-6 rats. 2. Bath application of nicotine increased GDP frequency in a concentration-dependent manner. For example, nicotine (0.5-1 microM) enhanced GDP frequency from 0.05 +/- 0.04 to 0.17 +/- 0.04 Hz. This effect was prevented by the broad-spectrum nicotinic receptor antagonist dihydro-beta-erythtroidine (DHbetaE, 50 microM) and partially antagonized by methyllycaconitine (MLA, 50 nM) a competitive antagonist of alpha7 nAChRs. GDP frequency was also enhanced by AR-17779 (100 microM), a selective agonist of alpha7 nAChRs. 3. The GABA(A) receptor antagonist bicuculline (10 microM) and the non-NMDA glutamate receptor antagonist DNQX (20 microM) blocked GDPs and prevented the effects of nicotine on GDPs. In the presence of DNQX, nicotine increased GABA-mediated synaptic noise, indicating that this drug may have a direct effect on GABAergic interneurons. 4. Bath application of edrophonium (20 microM), a cholinesterase inhibitor, in the presence of atropine (1 microM), increased GDP frequency, indicating that nAChRs can be activated by ACh released from the septo-hippocampal fibres. This effect was prevented by DHbetaE (50 microM). 5. In the majority of neurons tested, MLA (50 nM) and DHbetaE (50 microM) reduced the frequency of GDPs with different efficacy: a reduction of 98 +/- 11 and 61 +/- 29 % was observed with DHbetaE and MLA, respectively. In a subset of cells (40 % in the case of MLA and 17 % in the case of DHbetaE) these drugs induced a twofold increase in GDP frequency. 6. It is suggested that, during development, nAChRs modulate the release of GABA, assessed as GDPs, through distinct nAChRs. The rise of intracellular calcium via nAChRs would further strengthen GABA-mediated oscillatory activity. This can be crucial for consolidation of synaptic contacts and for the fine-tuning of the developing hippocampus.
...
PMID:Regulation of GABA release by nicotinic acetylcholine receptors in the neonatal rat hippocampus. 1157 59

Mutations in ric-3 (resistant to inhibitors of cholinesterase) suppress the neuronal degenerations caused by a gain of function mutation in the Caenorhabditis elegans DEG-3 acetylcholine receptor. RIC-3 is a novel protein with two transmembrane domains and extensive coiled-coil domains. It is expressed in both muscles and neurons, and the protein is concentrated within the cell bodies. We demonstrate that RIC-3 is required for the function of at least four nicotinic acetylcholine receptors. However, GABA and glutamate receptors expressed in the same cells are unaffected. In ric-3 mutants, the DEG-3 receptor accumulates in the cell body instead of in the cell processes. Moreover, co-expression of ric-3 in Xenopus laevis oocytes enhances the activity of the C.elegans DEG-3/DES-2 and of the rat alpha-7 acetylcholine receptors. Together, these data suggest that RIC-3 is specifically required for the maturation of acetylcholine receptors.
...
PMID:The C. elegans ric-3 gene is required for maturation of nicotinic acetylcholine receptors. 1186 29

The last decade brought a considerable progress in pharmacotherapy of addiction. Basing on recently gained knowledge of mechanisms of development of addiction and the physiology of the brain reward system, several therapeutic strategies have evolved. The strategies aimed at targeting the basic mechanisms of addiction rely on the premises that addiction is caused by adaptive changes in the central nervous system and that craving, which is the main cause of relapse, depends on dopaminergic mechanisms and requires high general excitability. The pharmacological approach involves drugs that reduce neuronal adaptability by inhibiting the calcium entry to neurons both through voltage-gated channels (e.g. nimodipine) and NMDA receptors (e.g. memantine), and drugs that stimulate the inhibitory GABAergic system (gamma-vinyl-GABA, baclofen), Particular attention is paid to the compounds that may attenuate dopaminergic hyperactivity, without considerable suppression of tonic activity of dopaminergic neurons (e.g. BP 897, a partial dopamine D3 receptor antagonist). Specific strategies are aimed at interference with the action of particular drugs of addiction. An important group includes the agonistic therapies (known also as substitution or maintenance therapies) in which a long-acting agonist is used in order to reduce the action of the drugs of high addictive potential (e.g. methadone against heroin addiction or vanoxerine (GBR 12909) against psychostimulants). Other specific strategies aimed at reduction of the transport of molecules of addictive substances into the brain: the approaches involve preparation of antibodies that form complexes unable to cross blood-brain barrier or enzymes accelerating the metabolism of the compounds in the blood (e.g. variants of butyrylcholinesterase). A considerable progress has been made in combating the abuse of legal addictive substances, alcohol (naltrexone, acamprosate) and tobacco (bupropion). The prospects for developing effective pharmacotherapies against addiction are bright. Unfortunately, ideological and social implications, as well as the conflict of interest with illegal narcotic manufacturers and distributors, may considerably hamper the progress in combating addiction (e.g. difficulties in introduction of methadone).
...
PMID:Drug addiction. Part III. Pharmacotherapy of addiction. 1199 60

The pathophysiology of Alzheimer's disease is complex and involves several different biochemical pathways. These include defective beta-amyloid (Abeta) protein metabolism, abnormalities of glutamatergic, adrenergic, serotonergic and dopaminergic neurotransmission, and the potential involvement of inflammatory, oxidative and hormonal pathways. Consequently, these pathways are all potential targets for Alzheimer's disease treatment and prevention strategies. Currently, the mainstay treatments for Alzheimer's disease are the cholinesterase inhibitors, which increase the availability of acetylcholine at cholinergic synapses. Since the cholinesterase inhibitors confer only modest benefits, additional non-cholinergic Alzheimer's disease therapies are urgently needed. Several non-cholinergic agents are currently under development for the treatment and/or prevention of Alzheimer's disease. These include anti-amyloid strategies (e.g. immunisation, aggregation inhibitors, secretase inhibitors), transition metal chelators (e.g. clioquinol), growth factors, hormones (e.g. estradiol), herbs (e.g. Ginkgo biloba), nonsteroidal anti-inflammatory drugs (NSAIDs, e.g. indomethacin), antioxidants, lipid-lowering agents, antihypertensives, selective phosphodiesterase inhibitors, vitamins (E, B12, B6, folic acid) and agents that target neurotransmitter or neuropeptide alterations. Neurotransmitter receptor-based approaches include agents that modulate certain receptors (e.g. nicotinic, muscarinic, alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid [AMPA], gamma-aminobutyric acid [GABA], N-methyl-D-aspartate [NMDA]) and agents that increase the availability of neurotransmitters (e.g. noradrenergic reuptake inhibitors). Of these strategies, the NMDA receptor antagonist memantine is in the most advanced stage of development in the US and is already approved in Europe as the first treatment for moderately severe to severe Alzheimer's disease. Memantine is proposed to counteract cellular damage due to pathological activation of NMDA receptors by glutamate. Results with Ginkgo biloba have been mixed. Data for neurotrophic therapies and vitamin E (tocopherol) appear promising but require confirmation. NSAIDs and conjugated estrogens have not proven to be of value to date for the treatment of Alzheimer's disease. Statins may have a potential role in reducing the risk or delaying the onset of Alzheimer's disease, although this has yet to be confirmed in randomised trials. There are currently no data to support the use of statins as a treatment for dementia. This article provides an update on the current status of selected agents, focusing primarily on those agents with the most extensive clinical evidence at present.
...
PMID:Non-cholinergic strategies for treating and preventing Alzheimer's disease. 1242 Nov 15

This study was designed to investigate the effects of the cholinesterase inhibitors soman and pyridostigmine bromide (PB) on synaptic transmission in the CA1 field of rat hippocampal slices. Soman (1-100 nM, 10-15 min) decreased the amplitude of GABAergic postsynaptic currents (IPSCs) evoked by stimulation of Schaffer collaterals and recorded from CA1 pyramidal neurons. It also decreased the amplitude and frequency of spontaneous IPSCs recorded from pyramidal neurons. Whereas the maximal effect of soman on evoked GABAergic transmission was observed at 10 nM, full cholinesterase inhibition was induced by 1 nM soman. After 10-15-min exposure of hippocampal slices to 100 nM PB, GABAergic transmission was facilitated and cholinesterase activity was not significantly affected. At nanomolar concentrations, soman and PB have no direct effect on GABA(A) receptors. The effects of soman and PB on GABAergic transmission were inhibited by the m2 receptor antagonist 11-[[[2-diethylamino-O-methyl]-1-piperidinyl] acetyl]-5,11-dihydrol-6H-pyridol[2,3-b][1,4]benzodiazepine-6- one (1 nM) and the m3 receptor antagonist 4-diphenylacetoxy-N-methyl-piperidine (100 nM), respectively, and by the nonselective muscarinic receptor antagonist atropine (1 microM). Thus, changes in GABAergic transmission are likely to result from direct interactions of soman and PB with m2 and m3 receptors, respectively, located on GABAergic fibers/neurons synapsing onto the neurons under study. Although the effects of 1 nM soman and 100 nM PB were diametrically opposed, they only canceled one another when PB was applied to the neurons before soman. Therefore, PB, acting via m3 receptors, can effectively counteract effects arising from the interactions of soman with m2 receptors in the brain.
...
PMID:Low concentrations of pyridostigmine prevent soman-induced inhibition of GABAergic transmission in the central nervous system: involvement of muscarinic receptors. 1249 May 99

Cocaine abuse is a serious health problem in many areas of the world, yet there are no proven effective medications for the treatment of cocaine dependence. Preclinical studies suggest that the reinforcing effect of cocaine that promotes its abuse is mediated by blockade of the presynaptic dopamine transporter. This results in increased dopamine activity in the mesolimbic or meso-accumbens dopamine reward system of brain. Development of new medications to treat cocaine dependence has focused on manipulation of this dopamine system, either by direct action on dopamine binding sites (transporter or receptors) or indirectly by affecting other neurotransmitter systems that modulate the dopamine system. In principle, a medication could act via one of three mechanisms: (i) as a substitute for cocaine by producing similar dopamine effects; (ii) as a cocaine antagonist by blocking the binding of cocaine to the dopamine transporter; or (iii) as a modulator of cocaine effects by acting at other than the cocaine binding site. The US National Institute on Drug Abuse has a Clinical Research Efficacy Screening Trial (CREST) programme to rapidly screen existing medications. CREST identified four medications warranting phase II controlled clinical trials: cabergoline, reserpine, sertraline and tiagabine. In addition, disulfiram and selegiline (deprenyl) have been effective and well tolerated in phase II trials. However, selegiline was found ineffective in a recent phase III trial. Promising existing medications probably act via the first or third aforementioned mechanisms. Sustained-release formulations of stimulants such as methylphenidate and amfetamine (amphetamine) have shown promise in a stimulant substitution approach. Disulfiram and selegiline increase brain dopamine concentrations by inhibition of dopamine-catabolising enzymes (dopamine-beta-hydroxylase and monoamine oxidase B, respectively). Cabergoline is a direct dopamine receptor agonist, while reserpine depletes presynaptic stores of dopamine (as well as norepinephrine and serotonin). Sertraline, baclofen and vigabatrin indirectly reduce dopamine activity by increasing activity of neurotransmitters (serotonin and GABA) that inhibit dopamine activity. Promising new medications act via the second or third aforementioned mechanisms. Vanoxerine is a long-acting inhibitor of the dopamine transporter which blocks cocaine binding and reduces cocaine self-administration in animals. Two dopamine receptor ligands that reduce cocaine self-administration in animals are also undergoing phase I human safety trials. Adrogolide is a selective dopamine D(1) receptor agonist; BP 897 is a D(3) receptor partial agonist.A pharmacokinetic approach to treatment would block the entry of cocaine into the brain or enhance its catabolism so that less cocaine reached its site of action. This is being explored in animals using the natural cocaine-metabolising enzyme butyrylcholinesterase (or recombinant versions with enhanced capabilities), catalytic antibodies, and passive or active immunisation to produce anti-cocaine binding antibodies. A recent phase I trial of a "cocaine vaccine" found it to be well tolerated and producing detectable levels of anti-cocaine antibodies for up to 9 months after immunisation.
...
PMID:Agents in development for the management of cocaine abuse. 1523 92

Metabotropic gamma-aminobutyric acid receptors (GABA(B)Rs) play a critical role in inhibitory synaptic transmission in the hippocampus. However, little is known about a possible long-term effect requiring transcriptional changes. Here, using microarray technology and RT-PCR of RNA from cultured rat embryonic hippocampal neurones, we report the profile of genes that are up- or downregulated by activation of GABA(B)Rs by baclofen but are not changed by baclofen in the presence of the GABA(B)R antagonist CGP-55845A. Our data show, for the first time, regulation of transcription of defined mRNAs after specific GABA(B) receptor activation. The identified genes can be grouped into those encoding signal transduction, endocytosis/trafficking, and structural classes of proteins. For example, butyrylcholinesterase, brain-derived neurotrophic factor, and COPS5 (Jab1) genes were upregulated, whereas Rab8 interacting protein and Rho GTPase-activating protein 4 were downregulated. These results provide important baseline genomic data for future studies aimed at investigating the long-term effects of GABA(B)R activation in neurones such as their roles in neuronal growth, pathway formation and stabilization, and synaptic plasticity.
...
PMID:Profile of changes in gene expression in cultured hippocampal neurones evoked by the GABAB receptor agonist baclofen. 1578 95


<< Previous 1 2 3 4 5 6 Next >>

---