Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this study we investigated acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities and the molecular forms of these enzymes in the cerebrospinal fluid (CSF) of non-demented and demented Parkinsonian patients and in controls. The ratio of AChE to BChE activity was lower in the CSF of demented patients than in non-demented patients, although AChE and BChE activities and the molecular forms of AChE and BChE were the same in the different groups of patients. AChE activity in CSF did not vary according to the severity or duration of dementia associated with Parkinson's disease or with the disability stage of Parkinson's disease. BChE activity in CSF correlated with these clinical parameters, and patients with cerebral atrophy had higher BChE activity in CSF than those patients without atrophy. These alterations in the BChE activity of CSF may be related to gliosis which occurs in the degenerating brain tissue.
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PMID:Acetyl- and butyrylcholinesterase activity in the cerebrospinal fluid of patients with Parkinson's disease. 369 32

The molecular forms of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) were studied in frontal cortex (grey and white matter), postmortem, and in cerebrospinal fluid (CSF) of demented patients with Parkinson's disease compared to controls and non-demented parkinsonians. In the frontal cortex, AChE activity decreased significantly in both demented and non-demented parkinsonian subjects compared to controls; the 10S form of the enzyme was significantly lower in demented parkinsonians than in the non-demented subjects. The decrease in AChE activity was correlated with a decrease in choline acetyltransferase activity thought to reflect lesion of cholinergic neurones in the substantia innominata which innervate the cerebral cortex. BChE activity decreased only in the non-demented parkinsonians; in the demented subjects, BChE activity was at control levels. Similar results were obtained with grey and white matter, although absolute levels of the two enzymes were different in the two types of tissue, suggesting that the enzymes were affected in the cholinergic neurones before transport to cortical nerve terminals. No decreases in AChE or BChE activity were observed in the CSF of the patients studied. On the contrary, AChE and BChE levels were significantly higher in demented parkinsonian patients compared to the non-demented subjects.
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PMID:Acetylcholinesterase and butyrylcholinesterase in frontal cortex and cerebrospinal fluid of demented and non-demented patients with Parkinson's disease. 394 70

Acetylcholinesterase has an action in the central nervous system, independent of hydrolysis of acetylcholine. This study explored the possible interaction between the two molecules: the effects of acetylcholinesterase on the autoxidation of the catecholamine were tested, and, in turn, modification of the catalytic activity of the enzyme by products of dopamine oxidation were studied. Acetylcholinesterase selectively inhibited the speed of quinone production from dopamine as well as accumulation of hydrogen peroxide, whilst the rate of generation of superoxide was increased. Analysis of absorption spectra revealed the formation of a new product, which appeared after mixing acetylcholinesterase and dopamine in neutral pH. In all cases, butyrylcholinesterase was ineffective. Incubation of acetylcholinesterase in the presence of dopamine resulted in a significant decrease in the catalytic activity of the enzyme. The effects of application of preparations modifying autoxidation of dopamine (SOD, catalase, peroxidase) suggested that inactivation of the enzyme occurred as a result of the direct interaction of a quinone and/or semiquinone oxidation product with enzyme, as opposed to any effects of reactive oxygen species. Because acetylcholinesterase and dopamine are co-released from the neurons degenerating in Parkinson's disease, a direct chemical interaction between these two molecules could have significance both for the normal functioning of the substantia nigra and for related pathological states.
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PMID:A possible interaction between acetylcholinesterase and dopamine molecules during autoxidation of the amine. 774 5

1. Due to their involvement in the termination of neurotransmission at cholinergic synapses and neuromuscular junctions, cholinesterases are the target proteins for numerous drugs of neuro-psychopharmacology importance. 2. In order to perform structure-function relationship studies on human cholinesterases with respect to such drugs, a set of expression vectors was engineered, all of which include cloned cDNA inserts encoding various forms of human acetyl- and butyrylcholinesterase. These vectors were designed to be transcribed in vitro into their corresponding mRNA products which, when microinjected into Xenopus oocytes, are efficiently translated to yield their catalytically active enzymes, each with its distinct substrate specificity and sensitivity to selective inhibitors. 3. A fully automated microtiter plate assay for evaluating the inhibition of said enzymes by tested cholinergic drugs and/or poisons has been developed, in conjunction with computerized data analysis, which offers prediction of such inhibition data on the authentic human enzymes and their natural or mutagenized variants. 4. Thus, it was found that asp70-->gly substitution renders butyrylcholinesterase succinylcholine insensitive and resistant to oxime reactivation while ser 425-->Pro with gly70 gives rise to the "atypical" butyrylcholinesterase phenotype, abolishing dibucaine binding. 5. Furthermore, differences in cholinesterase affinities to physostigmine, ecothiophate and bambuterol were shown in these natural variants. 6. Definition of key residues important for drug interactions may initiate rational design of more specific cholinesterase inhibitors, with fewer side effects. This, in turn, offers therapeutic potential in the treatment of clinical syndromes such as Alzheimer's and Parkinson's disease, glaucoma and myasthenia gravis.
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PMID:Structure-function relationship studies in human cholinesterases reveal genomic origins for individual variations in cholinergic drug responses. 827 1

Alzheimer's disease (AD) and Parkinson's disease (PD) are genetically heterogeneous. Dipeptidyl carboxypeptidase 1 (DCP1) and butyrylcholinesterase (BCHE) genes may modify the risk of these disorders. We investigated whether common polymorphisms present in these genes operate as risk factors for AD and PD in Finnish subjects, independently or in concert with the apolipoprotein E epsilon4 allele (APOE epsilon4). Eighty late onset sporadic AD patients, 53 PD patients (34 of whom had concomitant AD pathology), and 67 control subjects were genotyped for the insertion (I)/deletion (D) polymorphism of DCP1 and the K variant of BCHE. In logistic regression analysis, the DCP1 *I allele in combination with APOE epsilon4 significantly increased the risk of AD (OR 30.0, 95% CI 7.3-123.7), compared to subjects carrying neither of the alleles. Similar analysis showed that the risk of AD was significantly increased in subjects carrying both the BCHE wild type (*WT/*WT) genotype and epsilon4 (OR 9.9, 95% CI 2.9-33.8), compared to those without this BCHE genotype and epsilon4. Further, the risk of PD with AD pathology was significantly increased for carriers of DCP1 *I and epsilon4 (OR 8.0, 95% CI 2.1-31.1). We thus conclude that, in Finns, interaction between DCP1 *I and epsilon4 increases the risk of AD as well as of PD with coexisting Alzheimer pathology, which underlines the importance of the DCP1 I/D polymorphism in the development of Alzheimer neuropathology, whereas the wild type BCHE genotype in combination with epsilon4 had a combined effect with regard to the risk of AD.
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PMID:Dipeptidyl carboxypeptidase 1 (DCP1) and butyrylcholinesterase (BCHE) gene interactions with the apolipoprotein E epsilon4 allele as risk factors in Alzheimer's disease and in Parkinson's disease with coexisting Alzheimer pathology. 1101 54

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

Parkinson's disease patients may suffer from cognitive impairment and behavioural problems such as apathy, personality changes, speech disturbances and visual hallucinations (Parkinson's disease dementia). However, there is currently no recommended treatment for Parkinson's disease dementia and antipsychotic agents can worsen extrapyramidal symptoms, making them unsuitable for patients with this condition. The observation that patients with Parkinson's disease dementia have extensive cholinergic deficits led to the hypothesis that cholinesterase inhibitors may provide benefits for patients with this condition. Here, we present a case series of patients with Parkinson's disease and dementia who we treated with rivastigmine, a dual inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) that shows brain region-selectivity. The introduction of rivastigmine led to improvements in cognitive and functional abilities, as well as the resolution of behavioural problems and visual hallucinations. Rivastigmine was well tolerated by our patients when the dose was escalated slowly, including one patient who had previously experienced severe side-effects with the AChE-selective inhibitor donepezil. Despite the large number and range of concomitant medications being received by the patients, no side-effects thought to be related to drug-drug interactions were reported. A large, placebo-controlled study is warranted to ascertain the full clinical profile of rivastigmine in Parkinson's disease dementia.
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PMID:Rivastigmine for the treatment of dementia and visual hallucinations associated with Parkinson's disease: a case series. 1224 Jul 87

Behavioral and psychological symptoms of dementia (BPSD) are a common manifestation of Alzheimer's disease (AD) and other dementia syndromes. Patients experience prominent and multiple symptoms, which are both distressing and a source of considerable social, health, and economic cost. Development of symptoms is in part related to progressive neurodegeneration and cholinergic deficiency in brain regions important in the regulation of behavioral and emotional responses including the cortex, hippocampus, and limbic system. Cholinesterase (ChE) inhibitors offer a mechanism-based approach to therapy to enhance endogenous cholinergic neurotransmission. Studies using ChE inhibitors have demonstrated their clear potential to improve or stabilize existing BPSD. Differences have been noted between selective acetylcholinesterase (AChE) inhibitors (donepezil and galantamine) and dual ChE inhibitors (rivastigmine) in terms of treatment response. While donepezil has shown efficacy in moderate to severe noninstitutionalized AD patients, conflicting results have been obtained in mild to moderate patients and in nursing home patients. Galantamine has been shown to delay the onset of BPSD during a five-month study but has been otherwise poorly studied to-date. Both donepezil and galantamine have not as yet demonstrated efficacy in reducing psychotic symptoms or in reducing levels of concomitant psychotropic medication use. Studies with the dual ChE inhibitor rivastigmine in mild to moderately severe AD and in Lewy body dementia (LBD) have shown improvements in behavioral symptoms including psychosis. Improvements have been maintained over a period of up to two years. In addition, institutionalized patients with severe AD have shown symptomatic benefits with a reduction in the requirement for additional psychotropic drugs following treatment with rivastigmine. The psychotropic properties associated with rivastigmine may in part be mediated through effects on butyrylcholinesterase. Current treatment options are limited for patients with dementia syndromes other than AD. However, data concerning rivastigmine in patients with LBD and preliminary studies in Parkinson's disease dementia and vascular dementia suggest a role for ChE inhibitors across the spectrum of dementia syndromes. Finally, studies that incorporated a delayed start design demonstrate that ChE inhibitors may delay the progression of BPSD.
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PMID:The ABC of Alzheimer's disease: behavioral symptoms and their treatment. 1263 79

The aim of this study was to investigate the effect of butyrylcholinesterase (BuChE) and acetylcholinesterase (AChE) on cell survival, neurite outgrowth and voltage-dependent calcium currents in developing rat ventral mesencephalic (VM) neurons. Both BuChE and AChE have been shown to promote neurite outgrowth in postnatnal preparations. However, the effect of these substances has never been investigated on rat embryonic VM cells, which are used in animal models of foetal transplantation as a treatment for Parkinson's disease. The effects of incubation with BuChE and tetrameric (G(4))- or monomeric (G(1))-AChE on cell survival and neurite outgrowth were characterised over a 7-day period on dopaminergic cells within embryonic VM cultures. The acute effects of these treatments on voltage-dependent calcium currents from embryonic VM cells were then investigated using whole-cell voltage-clamp recordings. The chronic effect of modulating voltage-dependent calcium channels was subsequently explored using the selective calcium channel antagonists omega-agatoxin IVA, omega-conotoxin GVIA, and nifedipine. The results presented here demonstrate firstly trophic effects of BuChE and G(4)- and G(1)-AChE upon dopaminergic neurite outgrowth, secondly that BuChE and G(4)- and G(1)-AChE have an inhibitory effect on voltage-dependent calcium currents, and finally that selective voltage-dependent calcium channel inhibitors also have trophic effects upon dopaminergic neurite outgrowth.
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PMID:Effects of acetylcholinesterase and butyrylcholinesterase on cell survival, neurite outgrowth, and voltage-dependent calcium currents of embryonic ventral mesencephalic neurons. 1463 19

Degeneration of nigrostriatal dopamine neurons and cholinergic cortical neurones are the main pathological features of Parkinson's disease (PD) and for the cognitive deficit in dementia of the Alzheimer' type (AD) and in dementia with Lewy bodies (DLB), respectively. Many PD and DLB subjects have dementia and depression resulting from possible degeneration of cholinergic and noradrenergic and serotonergic neurons. On the other hand, AD patients may also develop extrapyramidal features as well as depression. In both PD and AD there is, respectively, accumulation of iron within the melanin containing dopamine neurons of pars compacta and with in the plaques and tangle. It has been suggested that iron accumulation may contribute to the oxidative stress induced apoptosis reported in both diseases. This may result from increased glia hydrogen peroxide producing monoamine oxidase (MAO) activity that can generate of reactive hydroxyl radical formed from interaction of iron and hydrogen peroxide. We have therefore prepared a series of novel bifunctional drugs from the neuroprotective-antiapoptotic antiparkinson monoamine oxidase B inhibitor, rasagiline, by introducing a carbamate cholinesterase (ChE) inhibitory moiety into it. Ladostigil (TV-3326, N-propargyl-3R-aminoindan-5yl)-ethyl methylcarbamate), has both ChE and MAO-AB inhibitory activity, as potential treatment of AD and DLB or PD subjects with dementia Being a brain selective MAO-AB inhibitor it has limited potentiation of the pressor response to oral tyramine and exhibits antidepressant activity similar to classical non-selective MAO inhibitor antidepressants by increasing brain serotonin and noradrenaline. Ladostigil inhibits brain acetyl and butyrylcholinesterase in rats and antagonizes scopolamine-induced inhibition of spatial learning. Ladostigil like MAO-B inhibitor it prevents MPTP Parkinsonism in mice model and retains the in vitro and in vivo neuroprotective activity of rasagiline. Ladostigil, rasagiline and other propargylamines have been demonstrated to have neuroprotective activity in several in vitro and in vivo models, which have been shown be associated with propargylamines moiety, since propargylamines itself possess these properties. The mechanism of neuroprotective activity has been attributed to the ability of propargylamines-inducing the antiapoptotic family proteins Bcl-2 and Bcl-xl, while decreasing Bad and Bax and preventing opening of mitochondrial permeability transition pore. Iron accumulates in brain regions associated with neurodegenerative diseases of PD, AD, amyotrophic lateral sclerosis and Huntington disease. It is thought to be involved in Fenton chemistry oxidative stress observed in these diseases. The neuroprotective activity of propargylamines led us to develop several novel bifunctional iron chelator from our prototype brain permeable iron chelators, VK-28, possessing propargylamine moiety (HLA-20, M30 and M30A) to iron out iron from the brain. These compounds have been shown to have iron chelating and monoamine oxidase A and B selective brain inhibitory and neuroprotective-antiapoptotic actions.
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PMID:Bifunctional drug derivatives of MAO-B inhibitor rasagiline and iron chelator VK-28 as a more effective approach to treatment of brain ageing and ageing neurodegenerative diseases. 1562 Dec 13


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