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

Regional variation in the response of the thoracic aorta to contractile agonists has previously been demonstrated. Since the net contractile response reflects the interaction between smooth muscle activation and the release of endothelial substances, we hypothesize that agonist-stimulated release of endothelium-derived nitric oxide (NO) also varies along the length of the thoracic aorta. The distribution of thoracic aorta estrogen receptors is also regionalized. Since pregnancy augments the release of endothelium-derived NO by acetylcholine (ACh) in some arterial beds, we further hypothesize that pregnancy enhances the stimulated release of NO from the thoracic aorta. Aortae were removed from nonpregnant and near term pregnant guinea pigs and cut into ring segments numbered sequentially proximal to distal. The rings were suspended at their optimal passive tension and submaximally contracted with prostaglandin F2 alpha. Endothelium-derived NO-dependent relaxation to ACh increased moving proximal to distal along the aorta independent of pregnancy and ACh relaxation was unaffected by pretreatment with physostigmine to inhibit cholinesterase. The magnitude of the relaxation to carbachol among the different segments was similar to ACh. Pregnancy decreased the ED50 for ACh of segments from the middle and distal segments of the thoracic aorta. Relaxation to the NO donor sodium nitroprusside and the nonreceptor-mediated endothelium-dependent relaxing agent A23187 was uniform along the length of the aorta and independent of pregnancy. These experiments demonstrate regional variation in the stimulated release of endothelium-derived NO in the guinea pig thoracic aorta which is increased by pregnancy.
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PMID:Regionalization of endothelium-dependent relaxation in the thoracic aorta of pregnant and nonpregnant guinea pigs. 773 56

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

We have investigated the effects of (a) the cholinesterase inhibitor physostigmine and (b) drugs that are known to change intracellular cyclic GMP levels on the autoinhibition of acetylcholine release from rat hippocampal slices. Autoinhibition was triggered by submaximal electrical stimulation in both the absence and presence of physostigmine. The results obtained indicate that an unusual increase in the extracellular acetylcholine content, such as that induced by cholinesterase inhibition, is not essential for autoinhibition triggering. Dibutyryl cyclic GMP reduced significantly the stimulation-evoked acetylcholine release in the presence, but not in the absence, of atropine. Neither sodium nitroprusside nor glyceryl trinitrate exerted a dibutyryl cyclic GMP-like effect. NG-Nitro-L-arginine did not lessen the autoinhibition. These results indicate that an increase in the intracellular cyclic GMP level reduces acetylcholine release, and that the muscarinic receptor stimulation-nitric oxide synthesis-(soluble) guanylyl cyclase activation pathway is not involved in the cholinergic autoinhibition process.
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PMID:Effects of physostigmine and some nitric oxide-cyclic GMP-related compounds on muscarinic receptor-mediated autoinhibition of hippocampal acetylcholine release. 838 37

Identification of human parasympathetic preganglionic neurons in pontomedullary regions has been largely based on studies using cholinesterase histochemical procedures, and so far there is no adequate account of the location of these cells. Nitric oxide synthase (NOS) is present in brainstem parasympathetic preganglionic salivatory neurons in the rabbit (Zhu et al., 1996). In the present study we have used histochemical and immunohistochemical staining for NOS to examine possible preganglionic parasympathetic neurons in the human brainstem. We examined, in five human brains, the distribution, through the caudal pons and rostral medulla, of NOS-positive neurons in serial sections stained with NADPH diaphorase for histochemistry, and with antibodies against neuronal NOS peptide for immunohistochemistry. In scattered pontomedullary regions (rostral to the dorsal motor nucleus and the nucleus ambiguus) known to contain parasympathetic preganglionic neurons in animals, we observed groups of NOS-positive neurons which correspond in morphology and distribution with NOS-positive parasympathetic preganglionic neurons in rabbits. These neurons are probably parasympathetic preganglionic neurons in the human brainstem, involved in the control of lacrimation, salivation, oral and nasopharyngeal secretion, as well as the control of the dilation of extra- and intracranial blood vessels.
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PMID:Human brainstem preganglionic parasympathetic neurons localized by markers for nitric oxide synthesis. 881 79

Although at present there is no definitive treatment or cure for Alzheimer's disease, different pharmacological strategies are being actively investigated. At present, cholinergic therapy and nootropics and some neuronotrophic agents represent the available approaches to symptomatic treatment of Alzheimer's disease. The use of cholinesterase inhibitors (ChEI) constitutes the best cholinergic approach to increase acetylcholine levels. Available data suggest that about 15 to 40% of Alzheimer's disease patients show a varying degree of cognitive improvement while taking these medications; however, haematological complications (neutropenia or agranulocytosis), together with hepatotoxicity, need to be considered carefully. Recent data suggest that long term administration of nootropics may lead to a significant improvement of cognitive functions in Alzheimer's disease patients compared with untreated individuals, having excellent tolerability. Protocols for the intracerebroventricular administration of neuronotrophic substances are also ongoing. The most promising approaches for the future currently undergoing investigation involve attempts to slow the production of beta-amyloid and/or to inhibit beta-amyloid aggregation. Another rational therapeutic approach would be to inhibit the formation of paired helical filaments (PHF) by increasing and/or modulating the activities of protein phosphatases and kinases. Antioxidant therapy should disrupt or prevent the free radical/beta-amyloid recirculating cascade and the progressive neurodegeneration. Idebenone, a synthetic compound acting as an 'electron trapper' and free radical scavenger, has shown some efficacy in degenerative and vascular dementia; at present, other different molecules having antioxidative properties [lazaroids (21-aminosteroids), pyrrolopyrimidines, nitric oxide blockers, selegiline, some vitamins] are under investigation. Lowering absorption or brain tissue concentrations of aluminium also offers possible therapeutic opportunities for slowing the rate of clinical progression of the disease; in this sense, some evidence exists using the aluminium chelating agent deferoxamine (desferrioxamine). Inflammation also may play a significant pathogenetic role in Alzheimer's disease. As shown by several retrospective analyses, there is an inverse association of anti-inflammatory drug use with the frequency of Alzheimer's disease diagnosis. Consequently, clinical trials using both nonsteroidal and steroidal molecules have been proposed. These lines of pharmacological intervention represent an important premise for future therapeutic strategies capable of counteracting the pathogenesis of Alzheimer's disease.
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PMID:Cognitive enhancement therapy for Alzheimer's disease. The way forward. 912 64

Mechanisms of relaxation induced by nerve stimulation were examined in isolated porcine iris sphincter muscle in reference to norepinephrine, nitric oxide (NO) and vasoactive intestinal polypeptide (VIP) and the functional interaction of inhibitory and excitatory nerves. Changes in isometric tension were recorded in strips of the sphincter pupillae, which were stimulated by transmurally applied electrical pulses. The presence of neurons containing acetylcholinesterase and tyrosine hydroxylase (TH) was determined histochemically. Transmural electrical stimulation (0.5-20 Hz) produced a frequency-related contraction, which was reversed to a relaxation by atropine in prostaglandin F2alpha-contracted strips. The relaxant response was abolished by timolol and suppressed by metoprolol, a beta1-adrenoceptor antagonist, but was not influenced by butoxamine, a beta2-receptor antagonist. Norepinephrine-induced relaxations were also attenuated only by timolol and metoprolol. Treatment with NG-nitro-L-arginine, a NO synthase inhibitor, and [D-p-Cl-Phe6,Leu17]VIP, a VIP receptor antagonist, did not inhibit the neurogenic relaxation. Contractions induced by nerve stimulation were potentiated by timolol and physostigmine but not by the NO synthase inhibitor. In the sphincter muscle, cholinesterase- and TH-positive nerve fibers and bundles were histologically detected. It is concluded that porcine iris sphincter is innervated by cholinergic excitatory and adrenergic inhibitory nerves. The neurogenic relaxation is associated solely with activation of beta1 adrenoceptors by norepinephrine but is not mediated by NO or VIP.
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PMID:Mechanisms underlying the neurogenic relaxation of isolated porcine sphincter pupillae. 1019 8

A prominent feature of Alzheimer's disease (AD) pathology is an abundance of activated glia (astrocytes and microglia) in close proximity to the amyloid plaques. These activated glia overexpress a number of proteins that may participate in the progression of the disease, possibly by propagation of inflammatory and oxidative stress responses. The beta-amyloid peptide 1-42 (Abeta), a major constituent of neuritic plaques, can itself induce glial activation. However, little is known about whether other plaque components, especially the upregulated glial proteins, can induce glial activation or modulate the effects of Abeta on glia. In this study, we focused on four glial proteins that are abundant in amyloid plaques and/or that are known to interact with Abeta: alpha1-antichymotrypsin (ACT), interleukin-1beta (IL-1beta), S100beta, and butyrylcholinesterase (BChE). We examined the ability of these proteins to activate rat cortical astrocyte cultures and to influence the ability of Abeta to activate astrocytes. Treatment of astrocytes with ACT, IL-1beta, or S100beta resulted in glial activation, as assessed by reactive morphology, upregulation of IL-1beta, and production of inducible nitric oxide synthase and nitric oxide. The ability of Abeta to induce astrocyte activation was also enhanced in the presence of each of these three proteins. In contrast, BChE alone did not activate astrocytes and had no effect on Abeta-induced activation. These results suggest that certain proteins produced by activated glia may contribute to the chronic glial activation seen in AD through their ability to stimulate astrocytes directly or through their ability to modulate Abeta-induced activation.
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PMID:Glial-derived proteins activate cultured astrocytes and enhance beta amyloid-induced glial activation. 1052 94

The authors have for the first time evaluated the basic parameters of the voice using computed voice analysis in patients with myasthenia gravis (MG). The aim of the study was to introduce an objective method suitable for the assessment of dysphonic symptoms, which predominate in bulbar, oculobulbar and generalized MG. Voice profile studies included the evaluation of the singing voice range, voice dynamics, maximum phonation time, and mean fundamental frequency and intensity during speech. The characteristic of the stroboscopic picture was also determined. Investigations were carried out before and after the intake of Mestinon, a reversible cholinesterase inhibitor, and healthy subjects were used as a control group. In MG, the voice range and dynamics are badly impaired, maximum phonation time is shortened, the mean fundamental frequency during speech is increased, while the intensity is decreased. Mestinon resulted in an improvement in all these parameters, however, they were still impaired in comparison to the control subjects. Most changes were found to be statistically significant. The authors emphasize the role of the otolaryngologist and objective phoniatric methods in the evaluation of MG and other myasthenia-like neurological diseases. The use of these methods for the assessment of phoniatric symptoms in neurological diseases is highly recommended.
HNO 1999 Nov
PMID:[Phoniatric studies in myasthenia gravis patients]. 1060 89

Qing Nao Yi Zhi Fang (QNYZ), a traditional Chinese medicine, has been developed as a drug to be used for the prevention and treatment of vascular dementia. However, the mechanisms by which this drug affects vascular dementia remain unknown. We examined the effects of QNYZ serum on glutamate excitotoxicity in rat fetal cerebral neuronal cells in primary culture. Exposure of neuronal cells to glutamate leads to a decrease in the activities of cholinesterase, superoxide dismutase, and streptoavidin peroxidase, and an increase in lactate dehydrogenase release. These enzyme activities were restored to the levels in untreated cells by the addition of QNYZ serum. QNYZ serum suppressed the increased nitric oxide production induced by glutamate and prevented glutamate-mediated apoptosis. QNYZ serum also improved mitochondrial energy metabolism after glutamate exposure. These findings suggest that QNYZ has protective effects against glutamate-mediated excitotoxicity in neuronal cells during ischemic brain injury.
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PMID:Effects of a traditional Chinese medicine, Qing Nao Yi Zhi Fang, on glutamate excitotoxicity in rat fetal cerebral neuronal cells in primary culture. 1092 65

Pulmonary arteries from the Madison (M) strain relax more in response to acetylcholine (ACh) than those from the Hilltop (H) strain of Sprague-Dawley rats. We hypothesized that differences in endothelial nitric oxide (NO) synthase (eNOS) expression and function, metabolism of ACh by cholinesterases, release of prostacyclin, or endothelium-derived hyperpolarizing factor(s) (EDHF) from the endothelium would explain the differences in the relaxation response to ACh in isolated pulmonary arteries. eNOS mRNA and protein levels as well as the NO-dependent relaxation responses to thapsigargin in phenylephrine (10(-6) M)-precontracted pulmonary arteries from the M and H strains were identical. The greater relaxation response to ACh in M compared with H rats was also observed with carbachol, a cholinesterase-resistant analog of ACh, a response that was not modified by pretreatment with meclofenamate (10(-5) M). N(omega)-nitro-L-arginine (10(-4) M) completely abolished carbachol-induced relaxation in H rat pulmonary arteries but not in M rat pulmonary arteries. Precontraction with KCl (20 mM) blunted the relaxation response to carbachol in M rat pulmonary arteries and eliminated differences between the M and H rat pulmonary arteries. NO-independent relaxation present in the M rat pulmonary arteries was significantly reduced by 17-octadecynoic acid (2 microM) and was completely abolished by charybdotoxin plus apamin (100 nM each). These findings suggest that EDHF, but not NO, contributes to the strain-related differences in pulmonary artery reactivity. Also, EDHF may be a metabolite of cytochrome P-450 that activates Ca(2+)-dependent K(+) channels.
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PMID:EDHF contributes to strain-related differences in pulmonary arterial relaxation in rats. 1115 29


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