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

In a group of patients with Parkinson disease there was no difference in plasma DBH activity between cases treated with L-Dopa and not treated. These patients tend to have an elevated activity of erythrocyte AChE.
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PMID:Plasma dopamine-beta-hydroxylase and erythrocyte acetylcholinesterase in a group of patients with Parkinson disease. 65 Feb 7

Loss of cholinergic cells in the basal forebrain is associated with commensurate reductions in cortical acetylcholine-related enzyme activities in both Alzheimer's disease (AD) and Parkinson's disease (PD). Nerve cell loss from the cholinergic pontine tegmental nuclei also occurs. As the latter nuclei project to the diencephalon, we used frozen tissue from 5 controls, 5 PD and 5 AD cases to study the distribution of ChAT, AChE and [3H]nicotine binding in the thalamus and subthalamic nucleus. The anterior nuclear group and the mediodorsal nucleus showed high activities of ChAT and AChE together with relatively high levels of [3H]nicotine binding. The centromedian nucleus and subthalamic nucleus contained equally high levels of ChAT but negligible levels of [3H]nicotine binding. There were no significant changes in the levels of ChAT, AChE and nicotine binding in the PD and AD groups indicating that involvement of the pedunculopontine tegmental nucleus is likely to be a secondary retrograde phenomenon rather than part of a systematic cholinergic fibre degeneration.
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PMID:Parameters of cholinergic neurotransmission in the thalamus in Parkinson's disease and Alzheimer's disease. 196 58

The effect of the neurotoxicant, 1-methyl-4-phenylpyridinium ion (MPP+) on acetylcholinesterase (AchE) activity was investigated. The MPP+ was found to inactivate the enzyme in a dose dependent manner. The kinetic parameter, Km for the substrate (acetylthiocholine), was found to be 0.216 mM and Ki for MPP+ for the inactivation of AChE was found to be 0.197 mM. It was found that MPP+ is neither a substrate of AChE nor the time-dependent inactivator. The studies of reaction kinetics indicate the inactivation of AChE to be a linear mixed-type inhibition. The inactivation of AChE by MPP+ was partially recovered by either dilution or gel exclusion chromatography. These data suggest that once MPP+ enters the basal ganglia of the brain, it can inactivate the AChE and thereby increase the acetylcholine level in the basal ganglia, leading to potential cell dysfunction. It appears likely that the nigrostriatal toxicity by MPP+ leading to Parkinson's disease-like syndrome may, in part, be mediated via the AChE inactivation.
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PMID:Acetylcholinesterase inhibition by 1-methyl-4-phenylpyridinium ion, a bioactivated metabolite of MPTP. 830 94

The effect of the neurotoxicant 1-methyl-4-phenyl-2,3-dihydropyridinium ion (MPDP+) on acetylcholinesterase (AchE) activity was investigated. The MPDP+ was found to inhibit the enzyme in a dose-dependent manner. The kinetic parameter, Km, for the substrate acetylthiocholine was found to be 0.22 mM, and the Kis and Kii for MPDP+ inhibition of AChE were found to be 0.265 and 0.578 mM, respectively. It was found that MPDP+ is neither a substrate of AChE nor a time-dependent inactivator. The studies of reaction kinetics indicate the inhibition of AChE to be a noncompetitive inhibition. The inhibition of AchE by MPDP+ was virtually reversed by either dilution or gel exclusion chromatography. These data suggest that once MPDP+ enters the basal ganglia of the brain, it can inhibit the AChE and thereby increase the acetylcholine level in the basal ganglia, leading to potential cell dysfunction. It appears likely that the nigrostriatal toxicity by MPDP+ leading to Parkinson's disease-like syndrome may, at least in part, be mediated via the AChE inhibition.
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PMID:Inhibition of acetylcholinesterase by the neurotoxicant, 1-methyl-4-phenyl-2,3-dihydropyridinium ion. 895 Oct 45

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

Cholinesterase inhibitors are commonly used to improve cognition and treat psychosis and other behavioral symptoms in Alzheimer's disease, Parkinson's disease, and other neuropsychiatric conditions. However, mechanisms may exist that down-regulate the synaptic response to altered cholinergic transmission, thus limiting the efficacy of cholinomimetics in treating disease. Acetylcholinesterase knockout (AChE-/-) mice were used to investigate the neuronal adaptations to diminished synaptic acetylcholine (ACh) metabolism. The striatum of AChE-/- mice showed no changes in choline acetyltransferase activity or levels of the vesicular ACh transporter but showed striking 60% increases in the levels of the highaffinity choline transporter. This transporter takes choline from the synapse into the neuron for resynthesis of ACh. In addition, the striata of AChE-/- mice showed dramatic reductions in levels of the M1, M2, and M4 muscarinic ACh receptors (mAChRs), but no alterations in dopamine receptors or the beta2 subunit of nicotinic receptors. M1, M2, and M4 also showed decreased dendritic and cell surface distributions and enhanced intracellular localizations in striatal neurons of AChE-/- mice. mAChR antagonist treatment reversed the shifts in mAChR distribution, indicating that internalized receptors in AChE-/- mice can recover to basal distributions. Finally, AChE-/- mice showed increased sensitivity to mAChR antagonist-induced increases in locomotor activity, demonstrating functional mAChR down-regulation. mAChR downregulation in AChE-/- mice has important implications for the long-term use of cholinesterase inhibitors and other cholinomimetics in treating disorders characterized by perturbed cholinergic function.
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PMID:Altered striatal function and muscarinic cholinergic receptors in acetylcholinesterase knockout mice. 1464 60

The neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been shown to reversibly inhibit the activity of acetylcholinesterase. The inactivation of the enzyme was detected by monitoring the accumulation of yellow color produced from the reaction between thiocholine and dithiobisnitrobenzoate ion. The kinetic parameter, Km for the substrate (acetylthiocholine), was found to be 0.216 mM and Ki for MPTP inactivation of acetylcholinesterase was found to be 2.14 mM. The inactivation of enzyme by MPTP was found to be dose-dependent. It was found that MPTP is neither a substrate of AChE nor the time-dependent inactivator. The studies of reaction kinetics indicate the inactivation of AChE to be a linear mixed-type inhibition. The dilution assays indicate that MPTP is a reversible inhibitor for AChE. These data suggest that once MPTP enters the basal ganglia of the brain, it can inactivate the acetylcholinesterase enzyme and thereby increase the acetylcholine level in the basal ganglia of brain, leading to potential cell dysfunction. It appears that the nigrostriatal toxicity by MPTP leading to Parkinson's disease-like syndrome may, in part, be mediated via the acetylcholinesterase inactivation.
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PMID:Inactivation of acetylcholinesterase by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride. 1467 91

Exposure to agricultural insecticides, together with yet incompletely understood predisposing genotype/phenotype elements, notably increase the risk of Parkinson's disease. Here, we report findings attributing the increased risk in an insecticide-exposed rural area in Israel to interacting debilitating polymorphisms in the ACHE/PON1 locus and corresponding expression variations. Polymorphisms that debilitate PON1 activity and cause impaired AChE overproduction under anticholinesterase exposure were strongly overrepresented in patients from agriculturally exposed areas, indicating that they confer risk of Parkinson's disease. Supporting this notion, serum AChE and PON1 activities were both selectively and significantly lower in patients than in healthy individuals and in carriers of the risky polymorphisms as compared with other Parkinsonian patients. Our findings suggest that inherited interactive weakness of AChE and PON1 expression increases the insecticide-induced occurrence of Parkinson's disease.
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PMID:Acetylcholinesterase/paraoxonase interactions increase the risk of insecticide-induced Parkinson's disease. 1562 87

Current treatment of Alzheimer's disease comprises pharmacological therapy and psychosocial interventions for patients and caregivers in the context of a symptom and severity dependent management concept. Treatment is targeted towards the core symptoms of dementia (cognitive and functional deficits) and if necessary, towards the behavioral symptoms of dementia. The treatment of Alzheimer's dementia with acetylcholine esterase inhibitors (AChE-I; donepezil, galantamine, rivastigmine) and memantine is evidence-based and recommended. For all drugs, the highest tolerable dose should be given. The choice of AChE-I depends on the side-effects and interaction profile, as there is no convincing evidence of a relevant superiority of one of the drugs over another. Mixed dementia should be treated as Alzheimer's dementia. Treatment of vascular dementia with AChE-I or memantine is off-label and without convincing evidence. There is no convincing evidence for the treatment of frontotemporal dementia or Lewy body dementia. Rivastigmine is effective for the treatment of dementia with Parkinson's disease.
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PMID:[S3 guidelines on dementia. Symptomatic therapy of dementia]. 2127 96

Neurodegenerative diseases are complex disorders with several pathoetiological pathways leading to cell death. Rationally designed multi-targeted agents, or "multi-targeted designed drugs" (MTDD) show significant promise in preclinical studies as neuroprotective and disease-modifying agents. In this review, we highlight the use of chemical scaffolds that lend themselves exquisitely to the development of MTDDs in neurodegeneration. Notably, synthetic polycyclic cage compounds have served as scaffolds for novel voltage-gated calcium channel blockers, NMDA receptor antagonists, and sigma-receptor ligands - attractive targets in neurodegeneration. In an entirely different approach, compounds containing the thiazolidinedione moiety (referred to as glitazones) alter mitochondrial function through the mitochondrial protein mitoNEET, an attractive new drug target for the treatment of neurodegenerative diseases. The design strategy for yet another agent, ladostigil, employed the amalgamation of active chemical moieties of the AChE inhibitor rivastigmine, and the monoamine oxidase-B (MAO-B) inhibitor rasagiline, leading to a single compound that targets both enzymes simultaneously. Natural products have also served as design templates for several MTDD design studies. In particular, the stilbene scaffold has become popular in particular due to the neuroprotective effects of the non-flavonoid natural product resveratrol. Recently, stilbene scaffold-based compounds were developed to reduce - through chelation with metal ions that interact with beta-amyloid - both metal-induced beta-amyloid protein aggregation, and ROS generated from this aggregate. Other subtle modifications of the stilbene motif led to the creation of reversible, non-competitive MAO inhibitors. Finally, compounds derived from the xanthine scaffold afford neuroprotection in Parkinson's disease through mechanisms that include dual adenosine A2A receptor antagonism and MAO-B inhibition.
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PMID:Rationally designed multi-targeted agents against neurodegenerative diseases. 2341 Jan 61


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