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)

Carbon-11 labeled N-methylpiperidin-4-yl acetate ([11C]MP4A) and carbon-11 labeled N-methylpiperidin-4-yl propionate ([11C]MP4P) are acetylcholine analogues and have been successfully used for measurement of brain acetylcholinesterase (AChE) activity in vivo in humans. In Alzheimer's disease (AD), there is a significant loss of AChE activity in the cerebral cortex in association with mental decline. The reduction of AChE activity in the cerebral cortex is more remarkable in early-onset AD than late-onset AD. There is mild but significant reduction of AChE activity in the cerebral cortex, even in the early stage of Parkinson's disease (PD) without dementia. There is remarkable reduction of AChE activity in the entire cerebral cortex in both PD with dementia and dementia with Lewy bodies (DLB). In two patients with frontotemporal dementia with parkinsonism linked to chromosome 17, there was prominent reduction of AChE activity in the cerebral cortex and thalamus. In 12 patients with progressive supranuclear palsy, there was profound reduction of AChE activity in the thalamus but not in the cerebral cortex. In corticobasal degeneration, there is symmetrical loss of AChE activity in the sensori-motor cortex.
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PMID:[Imaging of brain acetylcholinesterase activity in dementias and extrapyramidal disorders]. 1821 Aug 7

It is essential to recognize and treat psychosis in Parkinson's disease for several reasons. Studies have shown that psychosis in Parkinson's disease patients is a strong risk factor for nursing home placement. Psychosis may be the greatest source of stress for caretakers of Parkinson's patients; it is often persistent, and its presence markedly increases mortality. Treatment of psychotic symptoms should occur only after potential medical and environmental causes of delirium have been eliminated or addressed. Initial pharmacologic changes should include limiting the patient's antiparkinsonian medications to those that are necessary to preserve motor function. Should that fail, an atypical antipsychotic is presently the treatment of choice. An emerging treatment option is acetylcholinesterase inhibitors. This article reviews what is currently known about the course, prognosis, and treatment strategies in Parkinson's disease psychosis.
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PMID:Course, prognosis, and management of psychosis in Parkinson's disease: are current treatments really effective? 1832 64

To elucidate characteristic changes of brain acetylcholinesterase (AChE) in cerebellar degenerative disorders. Eight patients with the cerebellar variant of multiple system atrophy (MSA-C), 7 patients with spinocerebellar ataxia type-3 (SCA-3), 3 patients with SCA-6, and 13 healthy age-matched volunteers participated in this study. Brain AChE activity was measured by [(11)C] N-methylpiperidin-4-yl propionate PET in all subjects. Brain AChE activities were significantly decreased in the thalamus (-27%) and the posterior lobe of cerebellar cortex (-36%) in patients with MSA-C and in the thalamus (-23%) in patients with SCA-3 compared with healthy controls (P < 0.01). Thalamic AChE activities of SCA-3 patients were negatively correlated with the unified Parkinson's disease rating scale motor subscore (P < 0.001). AChE activities were not significantly altered in the cerebral cortex in any disease group. Reduction of AChE activities in the thalamus and cerebellum in MSA and in the thalamus in SCA-3 suggest that cholinergic modulating drugs may have a role in the treatment of ataxia and other symptoms in these disorders.
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PMID:PET study of brain acetylcholinesterase in cerebellar degenerative disorders. 1841 83

Selegiline, an irreversible inhibitor of monoamine oxidase B used in the treatment of Parkinson's disease, has been demonstrated to have a potential cognition-improving effect in patients with Alzheimer's disease (AD) undergoing treatment with an acetylcholinesterase inhibitor donepezil. To confirm such clinical events, we investigated whether co-administration of donepezil with selegiline had a synergistic cognition-improving effect in an animal model of AD. Intracerebroventricular injection of amyloid beta protein fragment 25-35 [Abeta(25-35)] induced impairment of learning and memory in a Y-maze, novel object recognition and contextual fear conditioning tests. Either donepezil or selegiline alone improved the cognitive impairments in the Y-maze and conditioned fear learning tasks in Abeta(25-35)-injected mice, whereas donepezil, but not selegiline, failed to improve the impairment in a novel object recognition task. Co-administration of donepezil with selegiline, at doses that do not exert efficacy individually, significantly improved the deficits in all three tests, indicating a synergistic cognition-improving effect. These alleviating effects were antagonized by pretreatment with a muscarinic receptor antagonist scopolamine and a dopamine receptor antagonist haloperidol. These results suggest that selegiline potentiates the effect of donepezil on the cognitive impairment, and that the synergistic effect may be mediated through both the cholinergic and dopaminergic systems.
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PMID:Synergistic effects of selegiline and donepezil on cognitive impairment induced by amyloid beta (25-35). 1842 Feb 88

Dementia associated with Parkinson's disease (PD) ultimately develops in approximately 70% of patients with PD older than 80 years of age. The neuropathology of PD dementia (PDD) is likely multifactorial and affects several neuronal populations. There is evidence that PDD is associated with a cholinergic deficit, supporting the therapeutic role of cholinesterase inhibitors, which are already first-line agents in the treatment of Alzheimer's disease. Open-label and small controlled studies suggested a clinical efficacy of cholinesterase inhibitors in PDD. One large randomized placebo-controlled trial of 541 patients demonstrated that oral rivastigmine improved cognition, attention and executive functions, activities of daily living and behavioral symptoms after 6 months of treatment. Rivastigmine is a dual cholinesterase inhibitor, being effective on both acetylcholinesterase and butyrylcholinesterase. This paper reviews the pharmacokinetic and pharmacodynamic properties of rivastigmine (oral and transdermal administration). It also reviews evidence on clinical efficacy, safety and tolerability of the oral administration in PDD patients at doses of 3-12 mg/day.
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PMID:Rivastigmine in Parkinson's disease dementia. 1867 61

Recent studies have reported that smokers tend to be less susceptible to Parkinson's disease (PD) and the stimulation of nicotinic acetylcholine receptor (nAChR) is considered to confer a neuroprotective effect. Galantamine is an acetylcholinesterase inhibitor and an allosteric potentiating ligand for nAChRs. However, the effects of galantamine and nicotine on dopaminergic neurons remain unclear. This study evaluated the neuroprotective effects of galantamine and nicotine in a rat 6-hydroxydopamine (6-OHDA)-induced hemiparkinsonian model. 6-OHDA with or without galantamine and/or nicotine were injected into unilateral substantia nigra of rats. Although methamphetamine-stimulated rotational behavior and dopaminergic neuronal loss induced by 6-OHDA were not inhibited by galantamine alone, those were moderately inhibited by nicotine alone. In addition, 6-OHDA-induced neuronal loss and rotational behavior were synergistically inhibited by co-injection of galantamine and nicotine. These protective effects were abolished by mecamylamine, an nAChR antagonist. We further found that alpha7 nAChR was expressed on both tyrosine hydroxylase (TH)-immunopositive and TH-immunonegative neurons in the SNpc. A combination of galantamine and nicotine greatly suppressed 6-OHDA-induced reduction of TH-immunopositive/alpha7 nAChR-immunopositive neurons. These results suggest that galantamine synergistically enhances the neuroprotective effect of nicotine against 6-OHDA-induced dopaminergic neuronal loss through an allosteric modulation of alpha7 nAChR activation.
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PMID:Synergistic effect of galantamine on nicotine-induced neuroprotection in hemiparkinsonian rat model. 1884 94

Organophosphates (OPs), commonly used as insecticides, inhibit acetylcholinesterase, the enzyme responsible for the inactivation of synaptic acetylcholine, which results in elevated acetylcholine neurotransmission. Nigrostriatal dopamine neurons receive substantial cholinergic innervation and express a number of nicotinic acetylcholine receptor subunits. Since epidemiological data have implicated pesticides in the incidence of Parkinson's disease, the current experiment investigated how repeated, developmental exposure to the OPs chlorpyrifos (CPS) or methyl parathion (MPT) affects striatal dopamine levels and dopamine neuron gene expression. Newborn rats were treated daily via oral gavage with corn oil vehicle, CPS, or MPT from postnatal days (PND) 1-21. Rats were sacrificed at PND 22 and 50. Levels of dopamine and its metabolites 3,4 dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were measured in the striatum and mRNA expression was measured in the substantia nigra. At 22 days of age, CPS and MPT treatment had no effect on dopamine, DOPAC or HVA levels. At 50 days of age, CPS significantly elevated DOPAC levels and elevated dopamine turnover (DOPAC/dopamine) but did not affect dopamine or HVA levels. MPT had no significant effects on any of these parameters. Interestingly, both CPS and MPT treatments caused a significant alteration in the ratio of alpha7 to alpha6 nicotinic acetylcholine receptor (nAChR) subunit expression in the substantia nigra with a non-significant elevation in alpha6 and a reduction in alpha7 at 22 days. At 50 days of age, a significant elevation in alpha6 nAChR subunit was observed in the MPT treated rats. No differences in dopamine neuron transcription factors (Nurr1 or Lmx1b) or neurotransmission genes were observed. These data demonstrate that repeated exposure to OPs during postnatal maturation can have a significant effect on dopamine neurochemistry, primarily by modifying dopamine metabolism, which can persist for up to 1 month (CPS) and alter acetylcholine subunit expression (CPS and MPT).
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PMID:Repeated developmental exposure to chlorpyrifos and methyl parathion causes persistent alterations in nicotinic acetylcholine subunit mRNA expression with chlorpyrifos altering dopamine metabolite levels. 1897 31

Recommendations for treatment with specific antidementia drugs in Denmark are given on the basis of recent evidence. Such evidence supports treatment of mild to moderate Alzheimer's Disease (AD) with acetylcholinesterase inhibitors (AchEI), and moderate to severe AD with memantine. Combination therapy with these drugs can be considered in moderate AD. Dementia with Lewy bodies and Parkinson's disease with dementia should be treated with rivastigmine. There is not sufficient evidence to recommend treatment with AchEI or memantine in pure vascular dementia or frontotemporal dementia.
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PMID:[Treatment of degenerative dementia disorders--who should be treated?]. 1926 6

Impairment of attention and memory in patients with Alzheimer's disease (AD) is associated with significantly lower levels of acetylcholine. Inhibition of the breakdown of acetylcholine by blocking the enzymes acetylcholinesterase and butyrylcholinesterase with rivastigmine improves this cholinergic depletion. Thus rivastigmine administration provides established, effective, long-term symptomatic treatment in AD and Parkinson's disease (PD) patients with dementia. A sustained treatment with cholinesterase inhibitors in general may also induce a certain deterioration of fine motor behavior, which may play a crucial role in the treatment of PD patients with dementia. Recent studies show that this altered balance between dopamine and acetylcholine due to cholinesterase inhibition, with its possible negative impact on motion behaviour, does not present a major problem in clinical practice in AD patients and may be compensated for by modification of dopaminergic substitution in PD patients with dementia. However, progression of neurodegeneration increases the vulnerability for psychosis in AD and PD patients with dementia in combination with dehydration and often requires additional application of neuroleptics. Since classical neuroleptics increase extrapyramidal symptoms, atypical neuroleptics are used. Out of these, quetiapine shows a distinct lower anticholinergic (muscarinergic) potency with beneficial effects on cognition. This favors its use in combination with rivastigmine.
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PMID:Rivastigmine in the treatment of patients with Alzheimer's disease. 1930 May 54

Acetylcholine (ACh) and choline (Ch) play a critical role in cholinergic neurotransmission and the abnormalities in their concentrations are related to several neural diseases. Therefore, the in vivo determination of ACh and Ch is important to the research on neurodegenerative disorders. In this work, electrochemical biosensors based on poly(m-(1,3)-phenylenediamine) (pmPD) and polytyramine (PTy) modified enzyme electrodes were fabricated. The electropolymerized pmPD polymer was used to exclude interfering substances and the PTy layer facilitated the immobilization of acetylcholinesterase (AChE) and choline oxidase (ChOx). Then, ACh/Ch sensor and Ch sensor were coupled with microdialysis to produce a novel device, which provides a sensitive and selective method for simultaneous determination of ACh and Ch. This method has detection limits of 63.0+/-3.4 nM for ACh and 25.0+/-1.2 nM for Ch. The integrated device was successfully applied to assessing the impact of endogenous neurotoxin N-methyl-(R)-salsolinol [1(R),2-dimethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, (R)-NMSal] on ACh and Ch concentration, which is of great benefit to understand the pathogenesis of Parkinson's disease.
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PMID:A new microdialysis-electrochemical device for in vivo simultaneous determination of acetylcholine and choline in rat brain treated with N-methyl-(R)-salsolinol. 1952 11


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