Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acetyl- and butyryl-cholinesterase activities have been measured biochemically in normal brain tissue, in senile dementia of Alzheimer type and in mental disorders without Alzheimer-type abnormalities. Acetylcholinesterase was significantly reduced and butyrylcholinesterase significantly increased, compared with the normal, in the hippocampus and temporal cortex of the Alzheimer cases. No significant enzyme changes were seen in the other diseases investigated including multi-infarct dementia, schizophrenia and depression. There was no correlation between age and acetylcholinesterase activity, but a significant positive correlation between the butyrylcholinesterase activities with increasing age (60-90 years) was found in the hippocampus. The possible connection between cholinergic system pathology and these cholinesterase abnormalities in Alzheimer dementia is discussed.
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PMID:Changes in brain cholinesterases in senile dementia of Alzheimer type. 70 27

Necropsy brain tissue from normal (control) patients and patients with depression and dementia was examined for activities of various cholinergic components, and these related to the degree of senile plaque formation and extent of intellectual impairment. Choline acetyltransferase and acetylcholinesterase activities decreased significantly as the mean plaque count rose, and in depressed and demented subjects the reduction in choline acetyltransferase activity correlated with the extent of intellectual impairment as measured by a memory information test; muscarinic cholinergic receptor binding activity remained unchanged with increasing senile plaque formation but butyrylcholinesterase activity increased. The results suggest a close relation between changes in the cholinergic system and Alzheimer's dementia, but the precise role of the system in this disease remains to be elucidated.
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PMID:Correlation of cholinergic abnormalities with senile plaques and mental test scores in senile dementia. 71 62

Biochemical responses of animals to environmental chemicals (biochemical biomarkers) can give measures of exposure, and sometimes also toxic effect. They are particularly valuable where they can be used to measure the toxic effects of chemicals in the field, employing non-destructive sampling methods. Measurements of exposure are useful in the case of non-persistent chemicals (e.g. organophosphorus, carbamate, or pyrethroid insecticides) which are difficult or impossible to detect by chemical analysis. They can also be useful to provide an integrated measure of the level of exposure to a group of related chemicals. Biochemical biomarkers are likely to provide a measure of toxic effect, where they are based upon a molecular mechanism which underlies toxicity. A widely-used biochemical biomarker is cholinesterase depression, which may involve destructive sampling (brain acetylcholinesterase) or non-destructive sampling (serum butyrylcholinesterase). For genotoxic chemicals, techniques which measure DNA damage (e.g. detection of DNA adducts) provide a powerful tool in measuring environmental effects. The detection of biochemical changes caused by anticoagulant rodenticides (e.g. abnormal levels of clotting proteins in blood) provides another example of this approach. In general, the development of simple, sensitive, and specific assays that are 'user-friendly' would open the way for much wider use of biochemical biomarkers in environmental monitoring.
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PMID:Biochemical responses as indicators of toxic effects of chemicals in ecosystems. 147 Dec 5

Rats injected intravenously with monoclonal antibodies reactive with brain acetylcholinesterase (AChE) developed a prolonged depression of plasma AChE without changes in butyrylcholinesterase, lactic acid dehydrogenase, or hematocrit. One antibody, ZR1, accumulated in the brain and spinal cord. Within 3 days of injection, ZR1 bound to most of the AChE in cerebral cortex and certain other regions of the CNS. Examination of the molecular forms of cortical 10S AChE, whereas 4S AChE remained free. In vitro, however, ZR1 bound equally to solubilized 4S and 10S forms. These data provide direct evidence for the compartmentalization of different AChE forms in the CNS, 10S being mainly extracellular and 4S apparently intracellular. Development of a striking and persistent bilateral ptosis within hours of injection suggests that AChE in the autonomic nervous system is also accessible to antibodies and, furthermore, is the site of an immunopathological lesion. This novel model of cholinergic autoimmunity may have relevance for human neurological disorders of unknown etiology.
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PMID:Selective complexing of acetylcholinesterase in brain by intravenously administered monoclonal antibody. 229 14

The changes in brain acetylcholinesterase (AChE), acid phosphatase (APase), and 2',3'-cyclic nucleotide-3'-phosphohydrolase (CNP), and plasma butyrylcholinesterase (BuChE) activities were investigated in hens treated with a single, dermal dose (100-1000 mg/kg) of S,S,S-tri-n-butyl phosphorotrithioate (DEF). Three control groups consisted of hens left untreated, given a single, dermal dose of 500 mg/kg tri-o-cresyl phosphate (TOCP, positive control for organophophorous compound-induced delayed neurotoxicity), or 10 mg/kg O,O-diethyl O-4-nitrophenyl phosphorothioate (parathion, negative control). Brain AChE activity, determined 28 days after application, was significantly inhibited in hens given 500-1,000 mg/kg DEF and in TOCP- and parathion-treated hens. In contrast, brain APase and CNP activities were significantly higher in all treatments as compared with those of the untreated hens. Parathion, however, caused the least increase in these enzymatic activities as compared to DEF or TOCP. A single, dermal dose of DEF or TOCP also caused an initial decrease in plasma BuChE activity with maximum depression of enzymatic activity observed 1 to 7 days after administration. This decrease was dose dependent and the enzymatic activity showed partial recovery with time. Hens treated with single, dermal doses of DEF, ranging from 250 to 1000 mg/kg, developed ataxia which progressed to paralysis in some hens. Histopathologic examination revealed axon and myelin degeneration of the spinal cord and peripheral nerves of some hens. The severity and frequency of the neuropathologic lesions were dose dependent. Neurologic dysfunctions and neuropathologic lesions seen in DEF-treated hens were similar to those exhibited in TOCP-treated hens. While parathion produced acute cholinergic effects, it did not cause delayed neurotoxicity. The changes in brain and plasma enzymes are discussed in relation to their role in the pathogenesis of DEF-induced delayed neurotoxicity.
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PMID:Brain acetylcholinesterase, acid phosphatase, and 2',3'-cyclic nucleotide-3'-phosphohydrolase and plasma butyrylcholinesterase activities in hens treated with a single dermal neurotoxic dose of S,S,S-tri-n-butyl phosphorotrithioate. 395 29

CHF2819 is a novel orally active acetylcholinesterase inhibitor (AChEI) developed for the treatment of Alzheimer's disease (AD). CHF2819 is a selective inhibitor of AChE, it is 115 times more potent against this enzyme than against butyrylcholinesterase (BuChE). Moreover, CHF2819 is more selective for inhibition of central (brain) AChE than peripheral (heart) AChE. In vivo CHF2819, 0.5, 1.5, and 4.5 mg/kg p.o., significantly and in dose-dependent manner increased acetylcholine (ACh) levels in hippocampus of young adult rats. Moreover, aging animals, with lower basal ACh levels than young adult rats, also exhibit a marked increase in hippocampal levels of this neurotransmitter after administration of CHF2819. At 1.5 mg/kg p.o. CHF2819 attenuated scopolamine-induced amnesia in a passive avoidance task. Furthermore, it decreased dopamine (DA) levels and increased extracellular levels of 5-hydroxytryptamine (5-HT) in the hippocampus, without modifying norepinephrine (NE) levels. By oral administration to young adult rats CHF2819 did not affect extracellular hippocampal levels of glutamate (Glu), aspartate (Asp), gamma-aminobutyric acid (GABA), taurine (Tau), arginine (Arg) or citrulline (Cit). Functional observational battery (FOB) screening demonstrated that CHF2819 (1.5 and 4.5 mg/kg p.o.) does not affect activity, excitability, autonomic, neuromuscular, and sensorimotor domains, as well as physiological endpoints (body weight and temperature). CHF2819 induced, however, involuntary motor movements (ranging from mild tremors to myoclonic jerks) in a dose-dependent manner. The neurochemical and behavioral profiles of CHF2819 suggest that this orally active novel AChEI could be of clinical interest for the treatment of Alzheimer-type dementia associated with multiple neurotransmitter abnormalities in the brain. In particular, CHF2819 might be a useful therapeutic drug for AD patients with cognitive impairment accompanied by depression.
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PMID:CHF2819: pharmacological profile of a novel acetylcholinesterase inhibitor. 1207 May 26

Behavioural and psychological symptoms of dementia (BPSD) are among the most distressing manifestations of dementia and result in considerable social and economic costs. Practical, non-pharmacological approaches such as environmental and behavioural changes may provide some benefit for patients in managing mild BPSD. In addition, various pharmacological approaches to treatment have been employed, such as neuroleptics and atypical antipsychotics, which differ in neurochemical target and clinical effectiveness. Growing evidence suggests that the neurobiological basis of BPSD in Alzheimer's disease (AD) and related dementias is a loss of cholinergic neurones and a resultant decline in acetylcholine (ACh) in brain regions which regulate behavioural and emotional responses, such as the limbic system. This cholinergic deficit can be partly corrected by inhibiting cholinesterase enzymes (ChEs). Studies of ChE inhibitors have shown positive effects to improve or stabilise existing BPSD and delay the emergence of new behavioural symptoms. In placebo-controlled studies, donepezil has reported efficacy in non-institutionalised moderate to moderately severe patients over a period of 24 weeks, but has failed to demonstrate efficacy in mild to moderate AD and in institutionalised patients with severe disease. Galantamine has been shown to delay the onset of BPSD in mild to moderate AD patients in one placebo-controlled study, and improve BPSD in a similar study of patients with cerebrovascular disease or probable vascular dementia. Studies with rivastigmine have shown efficacy in placebo-controlled studies of mild to moderately severe AD and in patients with Lewy body variant AD. Institutionalised patients with severe disease also show symptomatic benefits in BPSD with rivastigmine, resulting in a reduction in concomitant psychoactive medication use. Symptom complexes responding to ChE inhibitors appear to differ - all agents improve apathy, depression and anxiety, while rivastigmine additionally improves hallucinations and delusions, possibility as a result of dual inhibition of acetylcholinesterase and butyrylcholinesterase. The presence of hallucinations has been shown to predict response to rivastigmine. Accumulating data from studies of ChE inhibitors suggest that early intervention and long-term treatment, in addition to providing cognitive benefits, improves BPSD and offers potential to enhance quality of life. Differences seen between the agents in terms of efficacy in BPSD, tolerability and safety profiles may be the result of differences in neuropharmacological profiles.
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PMID:Understanding and managing behavioural symptoms in Alzheimer's disease and related dementias: focus on rivastigmine. 1209 26

Multiple behavioural and psychological symptoms of dementia (BPSD) are commonly associated with all dementia subtypes, and worsen during disease progression. BPSD arise due to impairment of cholinergic function in the cortex, hippocampus and related limbic systems. Recent studies have investigated the effect of cholinesterase inhibitors on BPSD. The dual acetylcholinesterase/butyrylcholinesterase (AChE/BuChE) inhibitor rivastigmine was shown to have several potential advantages over the AChE-selective inhibitors donepezil and galantamine for the treatment of BPSD. Rivastigmine appears to be effective across the range of dementia severity from mild to severe, and across the spectrum of dementia (Alzheimer's disease [AD], the AD variant with Lewy bodies, Parkinson's disease dementia and vascular dementia subtypes). It also appears to have a disease-modifying potential. Rivastigmine improved a wider range of behavioural symptoms (apathy, anxiety/depression, hallucinations and delusions) than donepezil and galantamine (which improved apathy and depression/anxiety only). Unlike donepezil, rivastigmine reduced the need for psychotropic medications to treat BPSD. Dual inhibition of AChE and BuChE and brain-region selectivity through preferential inhibition of the G1 isoform of AChE may provide the underlying reasons for the apparently greater and broader efficacy of rivastigmine over AChE-selective inhibitors for the treatment of BPSD. However, randomised, controlled trials are required to compare dual inhibitors, such as rivastigmine, and AChE-selective agents, to confirm and quantify any differences in their effects on BPSD.
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PMID:The efficacy of cholinesterase inhibitors in treating the behavioural symptoms of dementia. 1213 65

Blood samples from lizards (Gallotia galloti) collected from two agricultural areas (Las Galletas and Punta del Hidalgo) and two reference areas on the Island of Tenerife (Canary Islands, Spain) were analyzed for butyrylcholinesterase (BChE) activity. Serum BChE activity was characterized first by in vitro experiments using selective substrates and inhibitors. Of the total cholinesterase (ChE) activity, 74% could be attributed to BChE activity. This portion of the total ChE activity was inhibited dose dependently by tetraisopropyl pyrophosphoramide and hydrolyzed the substrate butyrylthiocholine iodide. No enzyme inhibition was observed at high substrate concentration. Twenty-one lizards collected from agricultural sampling sites showed significant inhibition (p < 0.001) of BChE activity (mean +/- standard deviation [SD] of 4.66 +/- 2.63 micromol/min/ml for lizards from Las Galletas and 5.13 +/- 1.48 for lizards from Punta del Hidalgo) compared with BChE activity for lizards from the reference sites (6.35 +/- 1.75 micromol/min/ ml). Las Galletas had the highest number of lizards (22%) with significantly inhibited BChE activity. In vitro assays showed that 10(-4) M pyridine-2-aldoxime methochloride (2-PAM) reactivated dichlorvos- or paraoxon-inhibited BChE activity within a 60-min incubation period. Almost all serum samples with depressed BChE activity that were collected from lizards from agricultural areas responded to 2-PAM reactivation of enzyme activity (8-60% increase in enzyme activity). Reactivation by treatment with 2-PAM confirmed that the depression of BChE activity was attributable to organophosphorus (OP) compounds. Evaluation of BChE activity levels and the chemical reactivation of serum BChE activity in G. galloti using 2-PAM was found to be a sensitive indicator of G. galloti exposure to OP compounds.
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PMID:Evaluating reptile exposure to cholinesterase-inhibiting agrochemicals by serum butyrylcholinesterase activity. 1255 60

Degeneration of cholinergic cortical neurons is one of the main reasons for the cognitive deficit in dementia of the Alzheimer type (AD) and in dementia with Lewy bodies (DLB). Many subjects with AD and DLB have extrapyramidal dysfunction and depression resulting from degeneration of dopaminergic, noradrenergic and serotoninergic neurons. We prepared a novel drug, TV-3326 (N-propargyl-3R-aminoindan-5yl)-ethyl methylcarbamate), with both cholinesterase (ChE) and monoamine oxidase (MAO) inhibitory activity, as potential treatment of AD and DLB. TV-3326 inhibits brain acetyl and butyrylcholinesterase (BuChE) in rats after oral doses of 10-100 mg/kg. After chronic but not acute treatment, it inhibits MAO-A and -B in the brain by more than 70% but has almost no effect on these enzymes in the small intestine in rats and rabbits. The brain selectivity results in minimal potentiation of the pressor response to oral tyramine. TV-3326 acts like other antidepressants in the forced swim test in rats, indicating a potential for antidepressant activity. Chronic treatment of mice with TV-3326 (26 mg/kg) prevents the destruction of nigrostriatal neurons by the neurotoxin MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). In addition to ChE and MAO inhibition, the propargylamine moiety of TV-3326 confers neuroprotective activity against cytotoxicity induced by ischemia and peroxynitrite in cultured neuronal cells that results from prevention of the fall in mitochondrial membrane potential and antiapoptotic activity. These unique multiple actions of TV-3326 make it a potentially useful drug for the treatment of dementia with Parkinsonian-like symptoms and depression.
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PMID:A novel cholinesterase and brain-selective monoamine oxidase inhibitor for the treatment of dementia comorbid with depression and Parkinson's disease. 1278 40


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