Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.1.7 (acetylcholinesterase)
 28,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Genotoxicity of eight topically applied compounds was determined using the bone marrow micronucleus (MN) test and hair follicle nuclear aberration (NA) assay in CD1 mice. Twenty-four hours after a single treatment, cyclophosphamide (CY), applied at doses corresponding to 1/4, 1/8, 1/16, and 1/32 of the published dermal LD50, and N-methyl-N-nitrosourea (MNU), applied at 1/4, 1/8, and 1/16 of the published dermal LD50, were found to increase the incidence of NA in a dose-dependent manner. The frequency of MN was significantly increased only at the highest dose of CY. Using the same protocol, six pesticides applied in dimethyl sulfoxide (DMSO) at doses of 1/8, 1/16, and 1/32 of the dermal LD50 were investigated. Aminocarb and chlordane induced a dose-dependent increase in the frequency of NA, while there was an observed increase in NA incidence at only the highest doses of dichlorvos (DDVP), 4,4'-DDT (DDT), and 2,4-dichlorophenoxyacetic acid (2,4-D). No effect was observed with fenitrothion on nuclear aberrations in hair follicles. Except for the highest dose of chlordane, none of the pesticides tested positive in the bone marrow micronucleus test. Serum cholinesterase levels were reduced to 70 +/- 4.7% of the DMSO control level with DDVP, 57 +/- 8.2% with aminocarb, and 60.3 +/- 4.8% with fenitrothion, indicating some systemic activity with these topically applied agents. The data suggest that aminocarb, chlordane, DDVP, DDT, and 2,4-D are genotoxic as determined by the NA assay and that this assay may be more useful in detecting topically applied genotoxic agents than the more often used bone marrow micronucleus test.
 ...
PMID:Comparison of the activity of topically applied pesticides and the herbicide 2,4-D in two short-term in vivo assays of genotoxicity in the mouse. 208 12

The acetylcholinesterase reversible inhibitor N-octyl-1,2,3, 4-tetrahydro-9-aminoacridine (THA-C8) is a new synthesized derivative of tacrine (THA) characterized by an alkyl chain in the molecular structure which ameliorates the penetrability of the compound into the central nervous system. THA-C8 (0.1-5 mg/kg) significantly reduced spontaneous locomotor activity in CD1 mice at a dose of 3 mg/kg. Moreover, THA-C8 (0.2-2 mg/kg) significantly improved shuttle-box avoidance acquisition at doses (0.25, 0.3, 1 mg/kg) not affecting locomotion and that are much lower than the doses reported to be effective for THA in animal models. From the data reported it seems that the new compound could be interesting for therapeutic purposes.
 ...
PMID:Effects of the novel acetylcholinesterase inhibitor N-octyl-1,2,3, 4-tetrahydro-9-aminoacridine on locomotor activity and avoidance learning in mice. 1019 8

Prion diseases are neurodegenerative disorders characterized by accumulation of an aberrantly folded isoform (PrP(Sc)) of the normal prion protein (PrP(C)). Using in situ hybridization and immunohistochemistry, we have studied changes in the expression of neuropeptides, acetylcholinesterase and tyrosine hydroxylase in CD1 and FVB wild-type mouse strains, as well as in PrP(C) null mice and in mice overexpressing PrP(C) following intracerebral inoculation with RML or Me7 prions. In the immunohistochemical analysis, neuropeptide Y (NPY), enkephalin and dynorphin-like immunoreactivities increased in mossy fibers of CD1 and FVB mice inoculated with either RML- or Me7 prions, whereas cholecystokinin-like immunoreactivity was decreased. These changes in peptide levels were paralleled by an increase in the transcripts in granule cells for neuropeptide Y, enkephalin, and cholecystokinin. However, the dynorphin transcript was decreased in the granule cells. The changes occurred more rapidly in PrP(C)-overexpressing compared to wild-type mice, and could not be found at all in PrP(C)-knockout mice. These changes in peptide expression, which mostly occur before appearance of symptoms of disease, may reflect attempts to initiate protective and/or regenerative processes.
 ...
PMID:Changes in neuropeptide expression in mice infected with prions. 1662 Nov 65

The phenotypes of three mouse strains that carry the acetylcholinesterase knockout (AChE KO) mutation have been compared. The AChE KO mouse was developed from embryonic stem (ES) cells, originating from a 129/Sv blastocyst. Animals generated from strain 129/Sv suffer from dysgenesis of the corpus callosum and possibly a number of other neuroanatomical deficiencies. To determine the contribution of background genes to phenotype, 129/Sv AChE heterozygote (AChE+/-) mice were backcrossed 10 generations with wild-type inbred C57/BL6 (C57) mice and with wild-type outbred CD1(R) mice. AChE-/- mice in strains C57 and CD1died during seizures before postnatal day (P) 21, whereas mice in strain 129/Sv lived to adulthood.
 ...
PMID:Phenotype comparison of three acetylcholinesterase knockout strains. 1719 42

Chlorpyrifos (CPF) is a broad spectrum organophosphorus insecticide bioactivated in vivo to chlorpyrifos-oxon (CPFO), a very potent anticholinesterase. A great majority of available animal studies on CPF and CPFO toxicity are performed in rats. The use of mice in developmental neurobehavioural studies and the availability of transgenic mice warrant a better characterization of CPF-induced toxicity in this species. CD1 mice were exposed to a broad range of acute (12.5-100.0mg/kg) and subacute (1.56-25mg/kg/day from 5 to 30 days) CPF oral doses. Functional and biochemical parameters such as brain and serum cholinesterase (ChE) and liver xenobiotic metabolizing system, including the biotransformation of CPF itself, have been studied and the no observed effect levels (NOELs) identified. Mice seem to be more susceptible than rats at least to acute CPF treatment (oral LD(50) 4.5-fold lower). The species-related differences were not so evident after repeated exposures. In mice a good correlation was observed between brain ChE inhibition and classical cholinergic signs of toxicity. After CPF-repeated treatment, mice seemed to develop some tolerance to CPF-induced effects, which could not be attributed to an alteration of P450-mediated CPF hepatic metabolism. CPF-induced effects on hepatic microsomal carboxylesterase (CE) activity and reduced glutathione (GSH) levels observed at an early stage of treatment and then recovered after 30 days, suggest that the detoxifying mechanisms are actively involved in the protection of CPF-induced effects and possibly in the induction of tolerance in long term exposure. The mouse could be considered a suitable experimental model for future studies on the toxic action of organophosphorus pesticides focused on mechanisms, long term and age-related effects.
 ...
PMID:Cholinesterase inhibition and alterations of hepatic metabolism by oral acute and repeated chlorpyrifos administration to mice. 1738 47

Organophosphorus insecticides, as Chlorpyrifos (CPF), are widely used in agriculture and against household pests; these compounds receive an increasing consideration as potential endocrine disrupters. The aim of the present study was to examine the potential short- and long-term effects of CPF on thyroid and adrenal glands in CD1 mice following exposure at dose levels not inducing brain acetyl cholinesterase (AchE) inhibition, during gestational and/or postnatal vulnerable phases. Pregnant dams were treated with 0, 3, 6 mg/kg bw/day of CPF on gestational days 15-18. After delivery, pups were treated subcutaneously on postnatal days (PND) 11-14 with: 0, 1, 3 mg/kg bw/day of CPF. Serum thyroxin (T4), thyroid and adrenals histology and histomorphometry were evaluated in dams and in F1 mice. In dams at 6 mg/kg, decreased T4 levels and increased cell height in thyroid were observed, and adrenal histology showed a slightly increased vacuolization in the X-zone. In the F1, short-term morphological modifications (reduced follicular size at PND 2) and long-term morphological (increased necrotic follicular cells) and biochemical alterations (reduced serum T4 levels) were found at PND 150 with an apparent higher vulnerability of males. For the first time these results indicate that CPF exposure at dose levels not inducing brain AchE inhibition causes thyroid alterations in dams and in F1 CD1 mice. Thyroid may be a sensitive target to CPF developmental exposure possibly leading to long-term effects on thyroid function. Because thyroid plays a pivotal role in mammalian development, these findings can be relevant to humans.
 ...
PMID:Developmental exposure to chlorpyrifos induces alterations in thyroid and thyroid hormone levels without other toxicity signs in CD-1 mice. 1919 Jan 25

Induction of the rare readthrough variant of acetylcholinesterase (AChE-R) by an acetylcholinesterase (AChE) inhibitor or by stress was tested in four mouse strains that differ in their behavioural profiles on tests of anxiety and depression. BALB/C, C57Bl/6, C3H/He and CD-1 mouse strains were tested in the elevated plus maze in two sessions, separated by 48h. All strains, except CD-1, showed the expected reduction in open arm exploration on the second session. BALB/C and C3H mice spent a greater proportion of the time in the open arms on the first exposure, but spent more time immobile in the maze compared to the CD1 and C57 strains. Immobility was attenuated upon the second exposure in all strains, except the BALB/C mice. Real-time PCR was used to investigate regional and strain differences in induction of AChE-R mRNA following four daily injections of diisopropylfluorophosphate (DFP) (.1mg/kg). AChE-R induction was found in the frontal cortex, but not in amygdala, hippocampus or striatum of CD-1 mice. Nor was there AChE-R induction in the brains of the inbred strains. Four daily sessions of swim stress were used to investigate stress-induced induction of AChE-R. BALB/C mice showed significantly more immobility in the forced swim test (FST) compared to the other strains. FST did not induce AChE-R mRNA in any brain region tested; however, AChE-R mRNA expression in the frontal cortex was negatively correlated with immobility in the FST.
 ...
PMID:Strain and regional dependence of alternate splicing of acetylcholinesterase in the murine brain following stress or treatment with diisopropylfluorophosphate. 2017 19

Diabetic encephalopathy describes the moderate cognitive deficits, neurophysiological and structural central nervous system changes associated with untreated diabetes. It involves neurotoxic effects such as the generation of oxidative stress, the enhanced formation of advanced glycation end-products, as well as the disturbance of calcium homeostasis. Due to the direct connection of choline (Ch) with acetylcholine availability and signal transduction, a background of Ch-deficiency might be unfavorable for the pathology and subsequently for the treatment of several metabolic brain diseases, including that of diabetic encephalopathy. The aim of this study was to shed more light on the effects of adult-onset streptozotocin (STZ)-induced diabetes and/or Ch-deprivation on the activities of acetylcholinesterase (AChE) and two important adenosine triphosphatases, namely Na(+),K(+)-ATPase and Mg(2+)-ATPase. Male adult Wistar rats were divided into four main groups, as follows: control (C), diabetic (D), Ch-deprived (CD), and Ch-deprived diabetic (D+CD). Deprivation of Ch was provoked through the administration of Ch-deficient diet. Both the induction of diabetes and the beginning of dietary-mediated provoking of Ch-deprivation occurred at the same day, and rats were killed by decapitation after 30 days (1 month; groups C1, D1, CD1 and D1+CD1) and 60 days (2 months; groups C2, D2, CD2 and D2+CD2, respectively). The adult rat brain AChE activity was found to be significantly increased by both diabetes (+10%, p < 0.001 and +11%, p < 0.01) and Ch-deprivation (+19%, p < 0.001 and +14%, p < 0.001) when compared to the control group by the end of the first (C1) and the second month (C2), respectively. However, the Ch-deprived diabetic rats' brain AChE activity was significantly altered only after a 60-day period of exposure, resulting in a +27% increase (D2+CD2 vs. C2, p < 0.001). Although the only significant change recorded in the brain Na(+),K(+)-ATPase activity after the end of the first month is attributed to Ch-deprivation (+21%, p < 0.05, CD1 vs. C1), all groups of the second month exhibited a statistically significant decrease in brain Na(+),K(+)-ATPase activity (-24%, p < 0.01, D2 vs. C2; -21%, p < 0.01, CD2 vs. C2; -22%, p < 0.01, D2+CD2 vs. C2). As concerns Mg(2+)-ATPase, the enzyme's activity demonstrates no significant changes, with the sole exception of the D2+CD2 group (+21%, p < 0.05, D2+CD2 vs. C2). In addition, statistically significant time-dependent changes concerning the brain Mg(2+)-ATPase activity were recorded within the diabetic (p < 0.05, D2 vs. D1) and the Ch-deprived (p < 0.05, CD2 vs. CD1) rat groups. Our data indicate that Ch-deprivation seems to be an undesirable background for the above-mentioned enzymatic activities under untreated diabetes, in a time-evolving way. Further studies on the issue should focus on a region-specific reevaluation of these crucial enzymes' activities as well as on the possible oxidative mechanisms involved.
 ...
PMID:Choline-deprivation alters crucial brain enzyme activities in a rat model of diabetic encephalopathy. 2083 65