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)

In a survey of occupationally acquired disease in workers at a pesticide plant, we found that 11 (11%) of 102 workers had been hospitalized for illness related to chemical exposures; highest hospitalization rates occurred in packaging (27%), production (22%), and maintenance (9%) workers. Commonest causes of hospitalization were intoxication by the carbamate pesticide methomyl [1-(methylthio)ethylideneamino methyl carbamate], a reversible cholinesterase inhibitor, and methemoglobinemia following exposure to 3,4-dichloroaniline. On clinical evaluation, five (46%) of 11 packaging workers, the group with the highest exposure to methomyl, had experienced blurred vision or pupillary constriction. Seventeen (61%) of 28 production workers with exposure to dichloroaniline and propanil (3'4'-dichloropropionanilide) had chloracne, an acne-form dermatosis caused by the contaminant tetrachlorazobenzene in propanil and dichloroaniline. The chloracnegenic potentials of propanil and dichloroaniline were verified by rabbit ear tests. These findings reemphasize the hazards inherent in the the manufacture and formulation of pesticides and herbicides.
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PMID:Propanil-chloracne and methomyl toxicity in workers of a pesticide manufacturing plant. 15 54

The administration of 2-pyridine aldoxime methyl chloride (2-PAM Cl) is a standard part of the regimen for treatment of human overexposure to many organophosphorus pesticides and nerve agents. However, some literature references indicate that poisoning by carbaryl (1-naphthyl N-methyl carbamate), an insecticide in everyday use, is aggravated by the administration of 2-PAM Cl. This effect has been reported in the mouse, rat, dog and man. We have found that the inhibition of both eel acetylcholinesterase (eel AChE, EC 3.1.1.7) and human serum cholinesterase (human BuChE, EC 3.1.1.8) by carbaryl was enhanced by several oximes. Based on 95% confidence limits the rank order of potentiation with eel AChE was TMB-4 = Toxogonin > HS-6 = HI-6 > 2-PAM Cl. By the same criterion, the rank order of potentiation with human BuChE was TMB-4 > Toxogonin > HS-6 = 2-PAM Cl. Carbaryl-challenged mice also reflected a potentiation since TMB-4 exacerbated the toxicity more than 2-PAM Cl. Our hypothesis is that certain oximes act as allosteric effectors of cholinesterases in carbaryl poisoning, resulting in enhanced inhibition rates and potentiation of carbaryl toxicity.
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PMID:Studies of the amplification of carbaryl toxicity by various oximes. 141 99

1-[(3-Fluoro-4-pyridinyl)amino]-3-methyl-1(H)-indol-5-yl methyl carbamate (P10358) is a potent, reversible acetylcholinesterase inhibitor that produces central cholinergic stimulation after oral and parental administration in rats and mice. P10358 is a 2.5 times more potent acetylcholinesterase inhibitor than THA in vitro (IC50 = 0.10 +/- 0.02 microM vs. IC50 = 0.25 +/- 0.03 microM). It also inhibits butyrylcholinesterase activity as potently as THA (IC50 = 0.08 +/- 0.05 microM vs. IC50 = 0.07 +/- 0.01 microM). Ex vivo, P10358 (0.2 - 20 mg/kg, p.o.) produced dose-dependent inhibition of brain acetylcholinesterase activity. At 10 and 20 mg/ kg, it produced profound and long-lasting hypothermia in mice. P10358 enhanced performance in rats in a step-down passive avoidance task (0.62 and 1.25 mg/kg) and in a social recognition paradigm (0.32, 0.64 and 1.25 mg/kg) in mice. It reversed scopolamine-induced deficits in the Morris Water maze in rats (1.25 and 2.5 mg/kg) and a higher dose elevated striatal homovanillic acid levels. These behavioral and biochemical effects are consistent with central cholinergic stimulation. Hemodynamic studies in the rat demonstrated a 16-fold separation between behaviorally active doses (1.25 mg/kg) and those that elevated arterial pressure (20 mg/kg). Lethality in rats occurred at an oral dose of 80 mg/kg, but not at lower doses. Chemically, P10358 is an N-aminoindole and may not have the hepatotoxic liability associated with aminoacridine structure of tacrine. P10358 had weak affinity (>10 microM) at a variety of aminergic and peptidergic receptors and uptake carriers. These properties suggest that P10358 may be a safe and promising symptomatic treatment for Alzheimer's disease.
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PMID:Pharmacological activity and safety profile of P10358, a novel, orally active acetylcholinesterase inhibitor for Alzheimer's disease. 902 83

TV3326, [(N-propargyl-(3R) aminoindan-5-yl)-ethyl methyl carbamate] is a novel aminoindan derivative of the selective irreversible monoamine oxidase (MAO)-B inhibitor, rasagiline (N-propargyl-(1R)-aminoindan), possessing both cholinesterase (ChE) and MAO-inhibitory activity. In doses of 35-100 micromoles/kg administered orally to rats, it inhibits ChE by 25-40% and antagonises scopolamine-induced impairments in spatial memory. After daily administration of 75 micromoles/kg for 2 weeks, TV3326 does not show any motor stimulant effects but significantly reduces immobility in the forced swim test, an action consistent with that of known antidepressants. This could result from more than 70% inhibition of both MAO-A and B in the brain that occurs under these conditions, since it is not shared by the S-isomer, TV3279, which does not block MAO. TV3326 also shows selectivity for brain MAO, even after 2 months of daily administration, with little or no effect on the enzyme in the intestinal tract and liver. This reduces the likelihood of it producing the "cheese effect" if administered with tyramine-containing foods or beverages. TV3326 and TV3279 protect against ischemia-induced cytotoxicity in PC12 cells and reduce the oedema, deficits in motor function and memory after closed head injury in mice. These neuroprotective effects do not result from MAO inhibition. The pharmacological actions of TV3326 could be of clinical importance for the treatment of AD, and the drug is currently in development for this purpose.
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PMID:TV3326, a novel neuroprotective drug with cholinesterase and monoamine oxidase inhibitory activities for the treatment of Alzheimer's disease. 1120 37

TV3326, (N-propargyl-(3R)-aminoindan-5-yl-ethyl,methyl carbamate) was prepared in order to combine the neuroprotective effects of rasagiline, a selective inhibitor of monoamine oxidase (MAO)-B with the cholinesterase (ChE) inhibitory activity of rivastigmine as a potential treatment for Alzheimer's disease. The study reported here examined the neuroprotective effects of TV3326 against various insults in vitro and in vivo. TV3326 caused a dose related (10-500 microM) reduction in death induced in NGF differentiated rat pheochromocytoma (PC12) cells by 3-4 hour exposure to oxygen-glucose deprivation. A single s.c. injection of TV3326 given five minutes after closed head injury in mice significantly reduced the cerebral edema, and accelerated the recovery of motor function and spatial memory several days later. Unilateral icv injection of streptozotocin (STZ) 1.5 mg in rats, caused specific damage to myelinated neurones in the fornix and corpus callosum accompanied by microgliosis. Three bilateral injections of STZ, 0.25 mg each, caused more widespread damage, and a marked impairment in spatial memory. Chronic oral treatment with TV3326 (75 mumols/kg) reduced the neuronal damage and microgliosis and almost completely prevented the memory impairment. The neuroprotective effect in PC12 cells may be due to a combination of ChE inhibition and antiapoptotic activity. The latter does not result from ChE inhibition. It is associated with the presence of the propargyl group, since it occurs with other propargylamines that do not inhibit MAO, but not with drugs that inhibit only ChE.
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PMID:Neuroprotective effects of novel cholinesterase inhibitors derived from rasagiline as potential anti-Alzheimer drugs. 1146 67

Two novel neuroprotective cholinesterase (ChE) inhibitors, TV3326, (N-propargyl-(3R) aminoindan-5-yl)-ethyl methyl carbamate, and TV3279, (N-propargyl-(3S) aminoindan-5-yl)-ethyl methyl carbamate, were derived from rasagiline for the treatment of Alzheimer's disease (AD). TV3326 also inhibits monoamine oxidase (MAO)-A and -B, whereas its S-isomer, TV3279, lacks MAO inhibitory activity. The action of these drugs in the regulation of amyloid precursor protein (APP) processing, using rat PC12 and human SH-SY5Y neuroblastoma cells, was examined. Both isomers stimulated the release of the non-amyloidogenic a-secretase form of soluble APP (sAPPalpha) from these cell lines. The increases in sAPPalpha, induced by TV3326 and TV3279, were dose-dependent (0.1-100 mM) and blocked by the hydroxamic acid-based metalloprotease inhibitor, Ro31-9790, suggesting mediation via a-secretase activity. Using several signal transduction inhibitors, we identified the involvement of protein kinase C (PKC), mitogen-activated protein (MAP) kinase, and tyrosine kinase-dependent pathways in the enhancement of sAPPalpha release by TV3326 and TV3279. In addition, both drugs directly induced the phosphorylation of p44 and p42 MAP kinase, which was abolished by the specific inhibitors of MAP kinase activation, PD98059 and U0126. These data suggest a novel pharmacological mechanism whereby these ChE inhibitors regulate the secretory processes of APP via activation of the MAP kinase pathway.
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PMID:Involvement of MAP kinase in the regulation of amyloid precursor protein processing by novel cholinesterase inhibitors derived from rasagiline. 1220 96

The anti Parkinson drug, rasagiline [R-(+)-N-propargyl-1-aminoindan], an inhibitor of type B monoamine oxidase, has been shown to suppress apoptosis induced by neurotoxins and oxidative stress. A series of novel propargylaminoindans with a carbamate moiety to inhibit cholinesterase were developed from phamacophore of rasagiline to protect or rescue deteriorated neurons in Alzheimer's and Lewy Body disease and provide a beneficial effect on the cognitive deficits. Rasagiline analogues were found to protect dopaminergic SH-SY5Y cells against apoptosis induced by peroxynitrite donor. SIN-1. TV3326, [(N-propargyl)-(3R)-aminoindan-5-yl]-ethyl methyl carbamate, was as effective as rasagiline in preventing apoptosis, followed by its S-enantiomer, TV3279. The anti-apoptotic-neuroprotective activity was shown to reside in the propargylamine and not the carbamate moiety. This resulted in stabilization of the mitochondrial membrane potential, the collapse of which initiates the apoptotic cascade.
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PMID:Anti-apoptotic action of anti-Alzheimer drug, TV3326 [(N-propargyl)-(3R)-aminoindan-5-yl]-ethyl methyl carbamate, a novel cholinesterase-monoamine oxidase inhibitor. 1269 91

Two novel neuroprotective cholinesterase (ChE) inhibitors, TV3326 and TV3279 [(N-propargyl-(3R) and (3S) aminoindan-5-yl)-ethyl methyl carbamate], respectively were derived from rasagiline, for the treatment of Alzheimer's disease (AD). TV3326 also inhibits monoamine oxidase (MAO)-A and B, while its S-isomer, TV3279, lacks MAO-inhibitory activity. The actions of these drugs in the regulation of the amyloid precursor protein (APP) processing using rat PC12 and human SH-SY5Y neuroblastoma cells were examined. Both isomers stimulated the release of the non-amyloidogenic alpha-secretase form of soluble APP (sAPPalpha) from these cell lines. The increases in sAPPalpha, induced by TV3326 and TV3279, were dose-dependent (0.1-100 micro M) and blocked by the hydroxamic acid-based metalloprotease inhibitor, Ro31-9790, suggesting mediation via alpha-secretase activity. Using several signal transduction inhibitors, the involvement of protein kinase C (PKC), mitogen-activated protein (MAP) kinase, and tyrosine kinase-dependent pathways in the enhancement of sAPPalpha release by TV3326 and TV3279 was identified. In addition, both drugs directly induced the phosphorylation of p44 and p42 MAP kinase, which was abolished by the specific inhibitors of MAP kinase activation, PD98059 and U0126. These data suggest a novel pharmacological mechanism, whereby these ChE inhibitors regulate the secretary processes of APP via activation of the MAP kinase pathway.
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PMID:Amyloid processing and signal transduction properties of antiparkinson-antialzheimer neuroprotective drugs rasagiline and TV3326. 1285 32

(R)-[(N-propargyl-(3R) aminoindan-5-yl) ethyl methyl carbamate] (TV3326) is a novel cholinesterase and brain-selective monoamine oxidase (MAO)-A/-B inhibitor. It was developed for the treatment of dementia co-morbid with extra pyramidal disorders (parkinsonism), and depression. On chronic treatment in mice it attenuated striatal dopamine depletion induced by MPTP and prevented the reduction in striatal tyrosine hydroxylase activity, like selective B and non-selective MAO inhibitors. TV3326 preferentially inhibits MAO-B in the striatum and hippocampus, and the degree of MAO-B inhibition correlates with the prevention of MPTP-induced dopamine depletion. Complete inhibition of MAO-B is not necessary for full protection from MPTP neurotoxicity. Unlike that seen after treatment with other MAO-A and -B inhibitors, recovery of striatal and hippocampal MAO-A and -B activities from inhibition by TV3326 did not show first-order kinetics. This has been attributed to the generation of a number of metabolites by TV3326 that cause differential inhibition of these enzymes. Inhibition of brain MAO-A and -B by TV3326 resulted in significant elevations of dopamine, noradrenaline and serotonin in the striatum and hippocampus. This may explain its antidepressant-like activity, resembling that of moclobemide in the forced-swim test in rats.
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PMID:Attenuation of MPTP-induced dopaminergic neurotoxicity by TV3326, a cholinesterase-monoamine oxidase inhibitor. 1287 70

The recent therapeutic approach in which drug candidates are designed to possess diverse pharmacological properties and act on multiple targets has stimulated the development of the bifunctional drug ladostigil (TV3326) [(N-propargyl-(3R) aminoindan-5yl)-ethyl methyl carbamate]. Ladostigil combines the neuroprotective effects of the antiparkinson drug rasagiline, a selective monoamine oxidase (MAO)-B inhibitor, with the cholinesterase (ChE) inhibitory activity of rivastigmine in a single molecule, as a potential treatment for Alzheimer's disease (AD) and Lewy Body disease. Here, we assessed the dual effects of lodostigil in terms of the molecular mechanism of neuroprotection and amyloid precursor protein (APP) regulation/processing by using an apoptotic model of neuroblastoma SK-N-SH cells. Ladostigil dose-dependently decreased cell death via inhibition of the cleavage and prevention of caspase-3 activation (IC50=1.05 microM) through a mechanism related to regulation of the Bcl-2 family proteins, which resulted in reduced levels of Bad and Bax and induced levels of Bcl-2 gene and protein expression. We have also followed APP regulation/processing and found that ladostigil markedly decreased apoptotic-induced levels of holo-APP protein without altering APP mRNA levels, suggesting a posttranscriptional mechanism. In addition, the drug-elevated phosphorylated protein kinase C (pPKC) levels and stimulated the release of the nonamyloidogenic alpha-secretase proteolytic pathway. Similar to ladostigil, its S-isomer, TV3279, which is a ChE inhibitor but lacks MAO inhibitory activity, exerted neuroprotective properties and regulated APP processing, indicating that these effects are independent of MAO inhibition.
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PMID:A multifunctional, neuroprotective drug, ladostigil (TV3326), regulates holo-APP translation and processing. 1693 43


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