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)

Multiple factors alter the interaction of muscle relaxants with the NMJ. This review has focused on the aberrant responses caused principally by alterations in AChRs (table 1). Many pathologic states increase (up-regulate) AChR number. These include upper and lower motor neuron lesions, muscle trauma, burns, and immobilization. Pre- or postjunctional inhibition of neurotransmission by drugs or toxins also up-regulate AChRs. These include alpha- and beta-BT, NDMR, anticonvulsants, and clostridial toxins. We speculate that other bacterial toxins also up-regulate AChR. With proliferation of AChRs, agonist drug dose-response curves are shifted to the left. The exaggerated release of potassium when depolarization occurs with the use of agonists such as SCh and decamethonium can be attributed to the increased number of AChR. Thus, SCh should be avoided in patients who are in the susceptible phase (see section V). In the presence of increased AChR, the requirement for NDMR is markedly increased. Thus, the response to NDMR may be used as an indirect estimator of increased sensitivity to SCh (table 1). The most extensively studied pathologic state in which there is a decrease in AChRs is myasthenia gravis; there is immunologically mediated destruction and/or functional blockade of AChRs. The pathophysiologic and pharmacologic changes in LEMS are quite distinct from those of myasthenia gravis. Decreased AChRs in myasthenia gravis result in resistance to agonists and increased sensitivity to competitive antagonists. In conditioning exercise, the perturbed muscles show sensitivity to NDMR that may be due to decreased AChRs. Chronic elevations of ACh observed with organophosphorus poisoning or chronic use of reversible cholinesterase inhibitors results in down-regulation of AChRs. In this condition, SCh should be avoided because its metabolic breakdown would be impaired; the requirement for NDMR may be decreased. All of the varied responses to SCh and NDMR, which are associated with concomitant changes in AChRs, are analogous to drug-receptor interactions observed in other biologic systems.
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PMID:Up-and-down regulation of skeletal muscle acetylcholine receptors. Effects on neuromuscular blockers. 842 65

Two cases of acquired autoimmune myasthenia gravis (MG) presenting transient amenorrhea were reported. Case 1, 28 years old, developed blepharoptosis and generalized fatigability at the age of 20 years. She had been treated only by anti-cholinesterase. Amenorrhea appeared at the age of 26 years. Then, physical examinations showed normal secondary sexual development and moderate myasthenic features. On laboratory examinations, SLE findings such as leucopenia (1,600/mm3), biologically false positivity in the serological tests for syphilis, negative Mantoux reaction, positive anti-nuclear and -DNA antibodies, were noted. Anti-AChR antibody was highly positive (max.: 353 nmol/l). Decreased E2 (13-15 pg/ml) and progesterone (0.21-0.29 ng/ml) values in serum, elevated LH (110-160 mIU/ml) and FSH (78-90 mIU/ml) and highly reactive LH-RH loading test were consistent with the hypergonadotropic hypogonadism. Thymus pathology of thymectomy which was done during amenorrhea, showed hyperplasia. Bilateral ovarian biopsy revealed a number of arrested primordial follicles, but neither inflammatory changes nor fibrosis. Immune complexes were not localized in the ovarian biopsy. The Kaufmann's therapy aggravated myasthenic symptoms. Menstruation recurred after 13 months of thymectomy. Amenorrhea continued for 18 months. Case 2, 37 years old, has had anti-epileptic regimens since the age of 4 years. She has been highly myasthenic for 15 years and treated by thymectomy, steroid hormone, plasmapheresis and some other therapies for 10 years. Amenorrhea occurred at the age of 34 years. Sexual development was normal. Myasthenia was very severe. On laboratory examinations, anti-AChR antibody was positive (max.: 941 nmol/l). Transient elevation of serum LH (37 mIU/l) and FSH (14 mIU/l) values was observed.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Two cases of myasthenia gravis associated with transient amenorrhea]. 279 17

Myasthenia gravis (MG) is an autoimmune disease of neuromuscular transmission associated with the presence of anti-acetylcholine receptor antibodies (anti-AChR Ab). Current treatment of MG includes anti-cholinesterase drugs, thymectomy, corticosteroids, immunosuppressants and plasma exchange (PE). The use of intravenous immune globulin (IVIG) in MG was proposed 10 years ago. Published results of IVIG treatment are discussed and the need for a controlled study is emphasized.
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PMID:Intravenous immune globulin in myasthenia gravis. 803 35

Acetylcholine (ACh) release from the motor nerve terminal in the streptozocin-induced diabetic state was studied in mouse phrenic nerve-diaphragm muscle preparations. Electrically evoked release of 3H-ACh from the preparation preloaded with 3H-choline was measured during two consecutive periods of stimulation (S1 and S2). In diabetic mice, the amount of 3H-ACh release during S2 was decreased, and the evoked ACh release declined more steeply with successive stimulation periods than in normal ddY mice. The decrease in release was restored when the presynaptic autoreceptors were stimulated by accumulating ACh under the irreversible inhibition of junctional cholinesterase by methanesulfonyl fluoride. This effect was abolished by the administration of (+)-tubocurarine (5 microM). In diabetic mice, the biphasic (acceleration and suppression) effect by succinylcholine on evoked ACh release was caused at 3- to 10-fold lower concentrations than in normal mice. The degree of enhancement of resting 3H-overflow by succinylcholine (10 and 30 microM) was greater in the diabetic state. These results indicated that in the diabetic state, the decrease in evoked ACh release interferes with its presynaptic action on inducing further release (positive feedback modulation) via the presynaptic nicotinic ACh receptor (n-AChR). The presynaptic hypersensitivity to succinylcholine may be due to the augmentation of presynaptic n-AChR sensitivity caused by the reduction of evoked ACh release in the diabetic state.
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PMID:Streptozocin-diabetes modifies acetylcholine release from mouse phrenic nerve terminal and presynaptic sensitivity to succinylcholine. 834 Oct 27

The aim of this work was to study gender differences on the physiology of the dimorphic brachial musculature involved in the clasp reflex of the toad (Bufo marinus L.). The neuromuscular transmission, the sensitivity to acetylcholine (ACh) and the cholinesterase activity were compared on the forelimb sternoradialis muscles (SR) from male and female toads. The interosseous muscles of the first finger were used to compare the properties of the nicotinic receptor/ionic channel complex (AChR). All the muscles studied were dimorphic, i.e. significantly smaller in the female than in the male frog in otherwise similar size animals. The SR of either sex contracted to bath application of ACh with similar EC50. In physiological solution the frequency of the miniature end-plate potentials (mepps) was very low (0.1 s-1) and no gender difference was detected. The mepp amplitudes were 0.62 +/- 0.03 and 0.58 +/- 0.03 mV in SR from male and female toads, respectively. To increase exocytosis the muscles were incubated in hypertonic solution (158 mM NaCl). Under this condition mepp frequency was increased by five and seven times and mepp amplitude increased by 1.3 and 1.6 times in SR from male and female toads, respectively. The cholinesterase activity measured by the colorimetric method, did not differ in SR from male and female toads. In muscle fibers dissociated from the dimorphic interosseous muscles of male and female toads, the ionic channel conductance was 43 +/- 5.3 and 44 +/- 4.5 pS, respectively. The mean channel open time was voltage-dependent and not significantly different in preparations from both genders. These observations indicate that neither the ACh-nicotinic receptor interaction, nor the AChR complex kinetics and the nicotinic excitation-contraction coupling or the cholinesterase activity differ in dimorphic muscles from Bufo genders. No gender difference was detected in neuromuscular transmission of the studied muscle. Only a slight increase in mepp frequency and amplitude could be detected when the muscles were incubated in hypertonic solution.
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PMID:Gender does not influence neuromuscular properties in dimorphic skeletal muscles of the toad. 988 74

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

The presence of acetylcholinesterase (AChE) mRNA and activity in the tissues and cells involved in immune responses prompted us to investigate the level and pattern of AChE components in spleen. AChE activity was higher in mouse spleen (0.46 +/- 0.13 micromol of acetylthiocholine split per hour and per mg protein) than in muscle or heart, but lower than in brain. The spleen was essentially free of butyrylcholinesterase (BuChE) activity. About 40% of spleen AChE was extracted with a saline buffer, and a further 40% with 1% Triton X-100. Sedimentation analyses, the splitting of subunits in AChE dimers, phosphatidylinositol-specific phospholipase C (PIPLC) exposure, and phenyl-agarose chromatography showed that hydrophilic (G1H, 43%) and amphiphilic AChE monomers (G1A, 36%), as well as amphiphilic dimers (G2A, 21%), occurred in spleen. All these molecules bound to fasciculin-2-Sepharose, although the extent of binding was higher for G1H (77%) than for G1A (63%) or G2A (48%) forms. Differences in the extent to which wheat germ lectin (WGA) adsorbed with AChE of mouse spleen and of erythrocyte allowed us to discard the blood origin of spleen AChE activity. A 62 kDa protein was labeled in spleen samples using antibodies against human AChE. The protein was attributed to AChE monomers since its size was the same, regardless of whether disulfide bonds were reduced or not. Since cholinergic stimulation modulates proliferation/maturation of lymphoid cells, AChE may be important for regulating the level of acetylcholine (ACh) in the neighborhood of cholinergic receptors (AChR) in spleen and other lymphoid tissues.
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PMID:Molecular properties of acetylcholinesterase in mouse spleen. 1508 30

The clinically achievable efficacy of the atypical antipsychotics on cognitive symptoms of schizophrenia is practically limited by their dose-dependent side effects. Thus, there is the need for adjuvant treatments or strategies for the cognitive impairments. Further, human autopsy and genetic data in schizophrenia have indicated the existence of the abnormality of nicotinic acetylcholine receptors (nAChR). In the present study, we aimed to investigate the synergistic effect and mechanisms of a combined treatment with an atypical antipsychotic risperidone and galantamine, which is a nAChR-allosteric modulator and a modest cholinesterase inhibitor, on the impairment of latent visuospatial learning and memory in mice resembling the cognitive impairment of schizophrenia. Repeated treatment with phencyclidine (PCP, 10 mg/kg, 14 days)-induced cognitive impairment in mice in a one trial water-finding test was used as a model of the cognitive impairment of schizophrenia. In vivo microdialysis was used to investigate the extracellular concentration of dopamine in the medial prefrontal cortex (mPFC). Combined treatment with galantamine and risperidone, at low, ineffective doses (both at 0.05 mg/kg) showed a synergistic effect to reverse cognitive impairment and increase extracellular concentration of dopamine in the mPFC. The synergistic behavioral effect was abolished by a dopamine-D1 receptor antagonist, SCH 23390, and a nAChR antagonist, mecamylamine, but not a muscarinic AChR (mAChR) antagonist, scopolamine. Mecamylamine also blocked the synergistic effect on dopamine release in the mPFC of PCP-treated mice. The study indicates that galantamine and risperidone may have synergistic effect on the cognitive impairments in schizophrenia patients by synergistically promoting the nAChR activation-dependent increase of dopamine D1 receptor-mediated neurotransmission.
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PMID:Synergistic effect of combined treatment with risperidone and galantamine on phencyclidine-induced impairment of latent visuospatial learning and memory: Role of nAChR activation-dependent increase of dopamine D1 receptor-mediated neurotransmission. 1763 85

First, we studied clinical effects of thymectomy on non-thymomatous ocular myasthenia gravis (MG) patients by comparing operative and non-operative groups. The QMG scores reduced with similar significances in both groups. Thymectomy is considered to be unnecessary in non-thymomatous ocular MG. Second, we discussed over the issue how elderly-onset MG patients could be treated. We believe that thymectomy is sufficiently tolerable and therefore could be selected with low dose oral prednisolone in moderate to severe MG cases. However we should be aware of various complications which are common in elderly patients. In mild cases, we can treat with anti-cholinesterase only. Third, we compared the long term effect of endoscopic thymectomy (infrasternal mediastinoscopic thymectomy) with conventional transsternal method. QMG scores and anti-AChR antibody titers reduced in both groups with similar significances suggesting that endoscopic thymectomy is as effective as transsternal thymectomy in treating MG.
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PMID:[Indication of thymectomy and immunotherapies on myasthenia gravis]. 1821 Aug 23

Myasthenia gravis (MG) with antibodies against the muscle-specific tyrosine kinase (MuSK abs) is often a severe disease requiring aggressive treatment. Various immunosuppressive (IS) regimens have been employed; the efficacy of plasma exchange is unanimously recognized, while the indication for thymectomy is controversial. We evaluated the response to therapy in 57 MuSK-positive patients (12 M/45 F) comparing our experience with other authors' results. Disease severity and response to treatment were graded according to MG Foundation of America; follow-up ranged from 0.5-29 years. Owing to both MG severity and the unsatisfactory response to cholinesterase inhibitors, most patients (54/57) needed IS treatment, and 35 received one or more courses of plasma exchange and intravenous immunoglobulin. At the end of follow-up, the rate of complete remission was 8.8%, and IS treatment had been withdrawn in only 10/54 patients. The extent of therapeutic response varied considerably. With conventional IS therapy (prednisone alone or in combination with azathioprine or cyclosporine), most patients achieved good control of their disease, but 30% of them were left with permanent facial and bulbar weakness. In patients with refractory disease, the use of mycophenolate mofetil and rituximab proved very effective, as also reported by other authors. In our and others' experience, MuSK-positive MG markedly improves with IS therapy, although, in comparison with the AChR-positive disease, it is characterized by a lower remission rate, as a higher proportion of patients remain dependent on treatment. Thymectomy is mostly considered scarcely effective; however, at present, no firm conclusions can be drawn on its role in the treatment of this form of MG.
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PMID:Response to therapy in myasthenia gravis with anti-MuSK antibodies. 1856 56


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