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)

The fall in body temperature and inhibition of hypothalamic cholinesterase induced by rivastigmine (a pseudo-reversible carbamate inhibitor) were compared in male and female rats. In males, 1.5 mg/kg lowered body temperature by 1 degrees C and in females by 3.2 degrees C (P<0.001) and inhibited cholinesterase by 65% and 74%, respectively (P<0.05). Pilocarpine (20 mg/kg) decreased body temperature by 1.1 degrees C in males and 1.9 degrees C in females (P<0.05). Orchidectomy, but not ovariectomy, abolished the sex difference in the hypothermic effect of pilocarpine and the enzyme inhibition induced by rivastigmine, but not in its effect on body temperature. Testosterone (10 mg/rat) decreased the cholinesterase inhibition and the temperature reduction induced by rivastigmine in gonadectomised males and females, but that induced by pilocarpine in males only. In conclusion, rivastigmine causes less inhibition of cholinesterase because testosterone may interfere with its entry into the brain. Testosterone may further decrease the temperature-lowering effect of rivastigmine and acetylcholine receptor agonists in males by an action at a receptor level.
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PMID:Testosterone mediates sex difference in hypothermia and cholinesterase inhibition by rivastigmine. 1175 36

A myriad of neurological symptoms including muscle and joint pain, ataxia, chronic fatigue, headache, and difficulty in concentration have been reported by Persian Gulf War (PGW) veterans. A large number of these veterans were prophylactically treated with pyridostigmine bromide (PB) and possibly exposed to sarin. In the present study we investigated the effects of PB and sarin, alone and in combination, on sensorimotor performance and the central cholinergic system of rats. Male Sprague-Dawley rats were treated with PB (1.3 mg/kg, 15 daily doses, oral) and sarin (50, 75, 90, and 100 microg/kg, single im dose on day 15), alone and in combination. The animals were evaluated for postural reflexes, limb placing, orienting to vibrissae touch, incline plane performance, beam-walk time, and forepaw grip time 7 and 15 days following treatment with sarin. Treatment with either PB or sarin alone resulted in significant sensorimotor impairments. Coexposure to sarin and PB resulted in significant sensorimotor deficits that worsened over time. By 15 days following sarin treatment, plasma butyrylcholinesterase (BChE) activity returned to normal levels in the animals treated with sarin alone, whereas in the animals exposed to PB or PB plus sarin, there was an increase in the enzyme activity. Cortical acetylcholinesterase (AChE) activity remained inhibited in the animals treated with sarin alone and in combination with PB. Muscarinic acetylcholine receptor (m2 mAChR) ligand binding with [(3)H]AFDX-384 in cortex and brain stem showed significant increases (approximately 120-130% of control) following coexposure to PB and sarin at higher doses. To evaluate the potential of PB for augmentation or inhibition of the toxicity induced by acute sarin exposure, the animals were exposed to either 10 or 100 microg/kg sarin (single im injection) with or without pretreatment with PB, and sacrificed 3 h after treatment with sarin. Pretreatment with PB offered slight protection in the plasma as well as brain regional enzyme activities. Pretreatment with PB did not have any effect on sarin-inhibited brain regional AChE activity following treatment with 100 microg/kg sarin. These results show that prophylactic treatment with PB offers some degree of protection in peripheral cholinesterase. Furthermore, these results show that treatment with either sarin or PB alone resulted in sensorimotor impairments, while coexposure to high doses of sarin with PB caused an exacerbated deficit.
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PMID:Sensorimotor deficit and cholinergic changes following coexposure with pyridostigmine bromide and sarin in rats. 1186 82

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.
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PMID:The C. elegans ric-3 gene is required for maturation of nicotinic acetylcholine receptors. 1186 29

In central nervous system, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) hydrolyse acetylcholine. Diminished cholinesterase activity is known to alter several mental and psychomotor functions. The symptoms of cholinergic crisis and those observed during acute attacks of acute intermittent porphyria are very similar. The aim of this study was to investigate if there could be a link between the action of some porphyrinogenic drugs on brain and the alteration of the cholinergic system. To this end, AChE and BuChE activities were assayed in whole and different brain areas. Muscarinic acetylcholine receptor (mAChR) levels were also measured. Results obtained indicate that the porphyrinogenic drugs tested affect central cholinergic transmission. Quantification of mAChR gave quite different levels depending on the xenobiotic. Veronal administration inhibited 50% BuChE activity in whole brain, cortex and hippocampus; concomitantly cortex mAChR was 30% reduced. Acute and chronic isoflurane anaesthesia diminished BuChE activity by 70-90% in whole brain instead cerebellum and hippocampus mAChR levels were only altered by chronic enflurane anaesthesia. Differential inhibition of cholinesterases in the brain regions and their consequent effects may be of importance to the knowledge of the mechanisms of neurotoxicity of porphyrinogenic drugs.
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PMID:The effects of some porphyrinogenic drugs on the brain cholinergic system. 1192 41

Mathematical modeling was applied to study the dependence of miniature endplate current (MEPC) amplitude and temporal parameters on the values of the rate constants of acetylcholine binding to receptors (k+) when cholinesterase was either active or inactive. The simulation was performed under two different sets of parameters describing acetylcholine receptor activation--one with high and another with low probability (Pohigh and Polow) of receptor transition into the open state after double ligand binding. The dependence of model MEPC amplitudes, rise times, and decay times on k+ differs for set Polow and set Pohigh. The main outcome is that for set Pohigh, the rise time is significantly longer at low values of k+ because of the prolongation of ACh diffusion time to the receptor. For the set Polow, the rise time is shorter at low values of k+, which can be explained by the small probability of AChR forward isomerization after ACh binding and faster MEPC's peak formation.
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PMID:Dependence of miniature endplate current on kinetic parameters of acetylcholine receptors activation: a model study. 1267 29

Cross-striated muscles of frogs and rats were fixed in 3.3 per cent lead nitrate solution. Frozen sections 30 micra thick were mounted in different media and observed by polarization microscopy. The subneural apparatus of myoneural junctions exhibits a strong birefringence in these sections. Birefringence is exerted by a highly organized lipoprotein framework (postsynaptic material) which builds up the "organites" (junctional folds) of the postsynaptic membrane. Synaptic cholinesterase is closely associated with this material. Freezing and/or formalin fixation results in a destruction of the molecular organization of the postsynaptic material, but does not influence the synaptic enzyme activity. It is hypothesized from this study that the junctional folds (postsynaptic "organites") consist of regularly arranged, sheet-like lamellar micellae in the frog and of less regular, mainly radially arranged submicroscopic units in the rat. The micellar organization as revealed by polarization analysis is in good agreement with the electron microscopic findings reported in the literature. Intramicellar protein molecules of the resting postsynaptic membrane are arranged longitudinally, lipids transversely. Supramaximal stimulation or treatment with acetylcholine + eserine results in a disorganization of proteins and a rearrangement of lipids. Denervation results in a rearrangement of lipids without any significant alterations of proteins. All these functional stresses influence only the molecular and not the micellar structure of the membrane. The function of the organized lipoprotein framework as an acetylcholine receptor is suggested.
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PMID:Submicroscopic organization of the postsynaptic membrane in the myoneural junction; a polarization optical study. 1402 37

The pathogenesis of myasthenia gravis (MG) involves a T cell-directed antibody-mediated autoimmune attack on the nicotinic acetylcholine receptor (AChR) or, occasionally, on other postsynaptic antigens. The antibodies induce their effects through complement-mediated destruction of the postsynaptic endplate membrane with resultant reduction in endplate AChR, and to a lesser degree by increased turnover of endplate AChR or blockade of AChR function. Considerable progress in the treatment of MG has accrued from so-called symptomatic treatments, including improved critical care of seriously ill patients and medications (e.g., cholinesterase inhibitors) increasing the concentration of acetylcholine at the remaining endplate AChRs. Information from other autoimmune diseases and from the response of the normal immune system to invading pathogens supports the view that the course of MG is characterized by exacerbations and remissions. Therefore, the goal in MG treatment is to induce and maintain a remission. This usually involves combinations of short-term and long-term immunosuppressive agents. Selection of the particular combinations of agents in a given patient is guided by the goal of minimizing the cost/benefit ratio of the regimen in an individual patient. In general, the plan involves an initial forceful attack followed by a slow and measured withdrawal.
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PMID:Treatment principles in the management of autoimmune myasthenia gravis. 1459 15

Autoimmune myasthenia gravis (MG) is associated with antibodies directed against the nicotinic acetylcholine receptor (AChR) in 85% of patients. Other postsynaptic neuromuscular junction antigens are implicated, e.g., muscle-specific receptor tyrosine kinase (MuSK), in a number of the remaining 15% of patients, so-called seronegative MG. The autoimmune attack generally leads to decreased concentrations of the AChR and damage to the structure of the endplate itself. This information has guided the empiric treatment of patients with MG and has suggested new treatment strategies. Whereas the outcome of patients with MG has improved because of more effective symptomatic treatment, including advances in critical care medicine and the use of cholinesterase inhibitors, the greatest advances have come from therapies that directly reduce the autoimmune attack or modify its effects on the AChR and the surrounding endplate. Immune-directed treatment of patients with MG, which is guided by this information and by data from the management of other autoimmune disease, is aimed at inducing an immunologic remission and then maintaining that remission. Remission induction is usually accomplished through the use of high-dose corticosteroids, frequently in conjunction with IV immunoglobulin or plasmapheresis. Maintenance of the remission is usually accomplished by slow tapering of the corticosteroids along with the use of "steroid-sparing" agents, which include azathioprine, thymectomy, and possibly mycophenolate. Therapy usually begins with cholinesterase inhibitors. If necessary, immune-directed treatment is added, beginning with either thymectomy or high-dose corticosteroids. The short-term therapies, i.e., IV immunoglobulin or plasmapheresis, may be effective in the early stages of treatment or later during an exacerbation. Steroid-sparing medications are usually added to facilitate the tapering phase.
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PMID:Treatment of autoimmune myasthenia gravis. 1545 26

Congenital Myasthenic Syndromes (CMS) are a heterogeneous group of diseases caused by genetic defects affecting neuromuscular transmission. The twenty five past Years saw major advances in identifying different types of CMS due to abnormal presynaptic, synaptic, and postsynaptic proteins. CMS diagnosis requires two steps: 1) positive diagnosis supported by myasthenic signs beginning in neonatal period, efficacy of anticholinesterase medications, positive family history, negative tests for anti-acetylcholine receptor (AChR) antibodies, electromyographic studies (decremental response at low frequency, repetitive CMAP after one single stimulation); 2) pathophysiological characterisation of CMS implying specific studies: light and electron microscopic analysis of endplate (EP) morphology, estimation of the number of AChR per EP, acetylcholinesterase (AChE) expression, molecular genetic analysis. Most CMS are postsynaptic due to mutations in the AChR subunits genes that alter the kinetic properties or decrease the expression of AChR. The kinetic mutations increase or decrease the synaptic response to ACh resulting respectively in Slow Channel Syndrome (characterized by a autosomal dominant transmission, repetitive CMAP, refractoriness to anticholinesterase medication) and fast channel, recessively transmitted. AChR deficiency without kinetic abnormalities is caused by recessive mutations in AChR genes (mostly epsilon subunit) or by primary rapsyn deficiency, a post synaptic protein involved in AChR concentration. Recently, mutations in SCN4A sodium channel have been reported in one patient. AChE deficiency is identified on the following data: recessive transmission, presence of repetitive CMAP, refractoriness to cholinesterase inhibitors, slow pupillary response to light and absent expression of the enzyme at EP. This synaptic CMS is caused by mutations in the collagenic tail subunit (ColQ) that anchors the catalytic subunits in the synaptic basal lamina. The most frequent presynaptic CMS is caused by mutations of choline acetyltransferase. Several CMS are still not characterized. Many EP molecules are potential etiological candidates. In these unidentified cases, other methods of investigations are required: linkage analysis, when sufficient number of informative relatives are available, microelectrophysiological studies performed in intercostal or anconeus muscles. Prognosis of CMS, depending on severity and evolution of symptoms, is difficult to assess, and it cannot not be simply derived from mutation identification. Most patients respond favourably to anticholinesterase medications or to 3,4 DAP which is effective not only in presynaptic but also in postsynaptic CMS. Specific therapies for slow channel CMS are quinidine and fluoxetine that normalize the prolonged opening episodes. Clinical benefits derived from the full characterisation of each case include genetic counselling and specific therapy.
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PMID:[Congenital myasthenic syndromes: phenotypic expression and pathophysiological characterisation]. 1503 73

Nicotinic acetylcholine receptor (nAChR) dysfunction occurs in individuals with schizophrenia (SZ) and may also affect individuals with bipolar disorder (BP). The molecular mechanisms for these disease-associated cholinergic deficits are not known. In vitro, the protein RIC-3 (resistance to inhibitors of cholinesterase-3) aids the assembly and trafficking of alpha7-nAChRs but has unclear action on the biogenesis of alpha4/beta2-nAChRs. To evaluate RIC-3/nAChR dynamics in diseased and normal human brain tissue, we measured RIC-3, alpha7-, alpha4- and beta2-nAChRs transcript levels in postmortem prefrontal cortex of individuals with SZ (n=31), BP (n=28) and unaffected controls (NC, n=33). Of the 28 individuals with BP, 20 had a history of psychotic symptoms. We compared relative message abundances between diagnostic groups and tested correlations of RIC-3 with each nAChR message subtype. RIC-3 and alpha4 messages were significantly increased in BP compared with NC (RIC-3, P< or =0.002; alpha4, P< or =0.04). RIC-3 message was also upregulated in SZ (P< or =0.04). In BP with psychoses, RIC-3 and alpha4 levels were increased compared with BP without psychoses (both P< or =0.02) and compared with NC (RIC-3, P< or =0.0003; alpha4, P< or =0.004). In correlation regression analyses, RIC-3 expression was very highly correlated to alpha7, alpha4 and beta2 in NC (alpha7, P< or =2.5e-05; alpha4, P< or =2.5e-09; beta2, P< or =0.003) and in SZ (alpha7, P< or =1e-07; alpha4, P< or =7e-07; beta2, P< or =3e-09). RIC-3 also strongly correlated with alpha7 and alpha4 in BP (alpha7, P< or =0.003; alpha4, P< or =3.5e-07). RIC-3 was modestly correlated with beta2 in BP overall (P< or =0.04), but showed no significant correlation in BP with psychoses (P< or =0.31) compared with a significant correlation in BP without psychoses (P< or =0.007). In conclusion, coordinated RIC-3/alpha4 upregulation and discordant RIC-3/beta2 levels suggest that alpha4/beta2 nAChR deficits in BP may occur from dysregulated RIC-3 chaperoning of the beta2 nAChR subunit in a subset of patients affected by psychotic features.
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PMID:Lack of RIC-3 congruence with beta2 subunit-containing nicotinic acetylcholine receptors in bipolar disorder. 1764 Aug 15


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