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)

Combined neuropathological and neurochemical assessment of the nucleus of Meynert in senile dementia of Alzheimer type (SDAT) have demonstrated that the cholinergic biochemical activity, choline acetyltransferase, is more extensively reduced in the nucleus (over 90%) than the loss of putative cholinergic perikarya (35%). Acetylcholinesterase histochemical activity was however substantially retained in individual neurones in the nucleus although virtually absent from the neocortex in SDAT. These abnormalities are consistent with a primary degeneration of cholinergic axons projecting to the cortex and secondary loss of perikarya from the subcortical nucleus. In contrast, preliminary observations on cases of Parkinson's disease suggest that the neuronal loss from the nucleus of Meynert may be greater in this disease than in SDAT, and previous studies have not consistently demonstrated a reduction in cortical choline acetyltransferase activities in Parkinson's disease. These observations, together with major differences in the neuropathology of the nucleus in SDAT and Parkinson's disease (neurofibrillary tangle and Lewy body formation, respectively) suggest that the involvement of the cholinergic system may differ in the two disease processes.
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PMID:Pathological changes in the nucleus of Meynert in Alzheimer's and Parkinson's diseases. 685 53

An in vitro mammalian model neuronal system to evaluate the intrinsic toxicity of soman and other neurotoxicants as well as the efficacy of potential countermeasures was investigated. The link between soman toxicity, glutamate hyperactivity and neuronal death in the central nervous system was investigated in primary dissociated cell cultures from rat hippocampus and cerebral neocortex. Exposure of cortical or hippocampal neurons to glutamate for 30 min produced neuronal death in almost 80% of the cells examined at 24 h. Hippocampal neurons exposed to soman for 15-120 min at 0.1 microM concentration caused almost complete inhibition (> or = 90%) of acetylcholinesterase but failed to show any evidence of effects on cell viability, indicating a lack of direct cytotoxicity by this agent. Acetylcholine (ACh, 0.1 mM), alone or in combination with soman, did not potentiate glutamate toxicity in hippocampal neurons. Memantine, a drug used for the therapy of Parkinson's disease, spasticity and other brain disorders, significantly protected hippocampal and cortical neurons in culture against glutamate and N-methyl-D-aspartate (NMDA) excitotoxicity. In rats a single dose of memantine (18 mg/kg) administered 1 h prior to a s.c. injection of a 0.9 LD50 dose of soman reduced the severity of convulsions and increased survival. Survival, however, was accompanied by neuronal loss in the frontal cortex, piriform cortex and hippocampus.
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PMID:Assessment of primary neuronal culture as a model for soman-induced neurotoxicity and effectiveness of memantine as a neuroprotective drug. 749 76

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

125I-Nerve growth factor (NGF) binding sites were analyzed by autoradiography in the striatum of 3 control subjects, 3 patients with Parkinson's disease and 3 patients with progressive supranuclear palsy. A high level of 125I-NGF binding was observed (0.3-0.4 fmol/mg of tissue equivalent) in the striatum and the nucleus basalis of Meynert of control patients. Pockets of lower 125I-NGF binding corresponding to acetylcholinesterase-poor striosomes were detected in the striatum of control subjects and patients with Parkinson's disease or progressive supranuclear palsy. When compared to controls, the density of 125I-NGF binding sites was reduced by 30% in the striatum of patients with progressive supranuclear palsy but not reduced in that of patients with Parkinson's disease. 125I-NGF binding was not significantly decreased in the nucleus basalis of Meynert in either diseases. Since NGF receptors are thought to be localized on cholinergic neurons in the striatum, the decrease in NGF binding is compatible with the loss of cholinergic neurons reported in the striatum from PSP patients.
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PMID:Loss of striatal high affinity NGF binding sites in progressive supranuclear palsy but not in Parkinson's disease. 789 88

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 distribution of the vesicular monoamine transporter was investigated post mortem in the human ventral mesencephalon of control subjects (n = 7) and patients with Parkinson's disease (n = 4) using tritiated dihydrotetrabenzine binding and autoradiography. Tritiated dihydrotetrabenazine binding was characterized by a single class of sites with a Kd of 7 nM and a Bmax of 180 fmol/mg of protein in the substantia nigra. Tritiated dihydrotetrabenazine binding sites were heterogeneously distributed in the mesencephalon of control subjects: the density of tritiated dihydrotetrabenazine binding sites was high in the substantia nigra pars compacta, locus coeruleus and nucleus raphe dorsalis, moderate in the ventral tegmental area and low in the substantia nigra pars reticulata and catecholaminergic cell group A8. Within the substantia nigra, a zone with maximal density of tritiated dihydrotetrabenazine binding, two times higher than the mean estimate for the whole substantia nigra pars compacta, was detected in the medial part of the structure. The anatomical organization of the human ventral mesencephalon was analyzed on adjacent sections stained for acetylcholinesterase histochemistry and tyrosine hydroxylase immunohistochemistry. Tritiated dihydrotetrabenazine binding displayed the same characteristic regional pattern of distribution as that observed with tyrosine hydroxylase immunohistochemistry except in the nucleus raphe dorsalis, where no tyrosine hydroxylase immunoreactivity was detected. In parkinsonian brains, the level of tritiated dihydrotetrabenazine binding was dramatically decreased in all regions of the ventral mesencephalon analyzed except in the substantia nigra pars reticulata. In the substantia nigra pars compacta, the reduction was by 55% for the whole structure and by 65% in its medial zone, where binding site density was maximal. In most nigral subsectors analyzed, the decrease in density of tritiated dihydrotetrabenazine binding sites reached the level expected given the loss of tyrosine hydroxylase-positive cells observed. By contrast, the ratio of [3H]dihydrotetrabenazine binding to the number of tyrosine hydroxylase positive neurons was significantly increased in the zone of high [3H]dihydrotetrabenazine binding sites. This relative sparing of tritiated dihydrotetrabenazine binding sites may be due either to the contribution of other monoaminergic neurons such as serotoninergic neurons or more likely to hyperactivity of the still surviving dopaminergic neurons.
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PMID:Regional distribution of monoamine vesicular uptake sites in the mesencephalon of control subjects and patients with Parkinson's disease: a postmortem study using tritiated tetrabenazine. 854 9

Sudomotor function in 83 patients with Parkinson's disease (PD) was evaluated using the sympathetic skin response (SSR) and sweat response to intradermal acetylcholine (ACh) injection. The incidence of abnormal SSRs (36.1%) increased, and the size of the response decrease with the severity of the illness. Neither the incidence of abnormal SSRs nor the amplitudes of the responses were influenced by levodopa or an anticholinergic agent. The SSR therefore can be used to evaluate the sudomotor efferent pathway in PD patients. In all the patients who had no SSR response, the local sweat response to ACh showed a reduced number of excitable sweat glands and low sweat volume. One patient, whose local sweat response to ACh was markedly impaired, had unmyelinated and acetylcholinesterase-positive fiber densities that were in the normal range in his biopsied sural nerve. The abnormal sweat response to ACh is considered to reflect the dysfunction of postganglionic sympathetic fibers in PD patients.
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PMID:Sympathetic skin response in Parkinson's disease. 874 Nov 31

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

Positron emission tomography with appropriate tracers provides unique opportunity to study neurotransmitter systems in the living human brain. PET with [18F] 6-fluoro-L-dopa (FD) provides an index of the integrity of nigrostriatal pathway, and striatal FD uptake correlates linearly with the density of nigral neurons. PET allows us to assess the progression of the nigral lesions in Parkinson's disease (PD). A 68-year-old normal female volunteer was scanned by FD-PET. Subsequently, she developed parkinsonism 3.7 years after the scan. A repeated FD-PET scan revealed a significant reduction of FD uptake by 20% over the 5.2 year interval. The results suggest a relatively short presymptomatic period with fast initial losses of nigral neurons in PD. FD-PET has been used to determine the viability of fetal graft implanted in the striatum for the treatment of PD. PET imaging of dopamine D1 and D2 receptors may be useful for the differential diagnosis of PD and striatonigral degeneration. PET reveals significant reduction of dopamine D1 and D2 receptor binding in the putamen of patients with SND, while D1 and D2 receptor binding is normal or slightly upregulated in PD. We found hypersensitivity of muscarinic cholinergic receptors in the frontal cortex of patients with PD by using PET. The result suggests a loss of ascending cholinergic system in the frontal cortex in PD, which may cause the frontal lobe dysfunction in PD. Recently, acetylcholine analogs labelled with positron emitter have been developed for measurement of brain acetylcholinesterase activity in vivo. These tracers may be useful for the assessment of ascending cholinergic system in Alzheimer's disease and PD.
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PMID:[Neurotransmitter systems in the human brain studied by positron emission tomography]. 912 90

The galanin (GAL) containing peptide fiber system innervates the basal forebrain and has been shown to hyperinnervate remaining cholinergic neurons in Alzheimer's disease (AD). GAL modulates the release of acetylcholine and, therefore, may depress this neurotransmitter in surviving cholinergic basal forebrain (CBF) neurons in AD. The aim of this study was to identify putative synaptic contacts between GAL immunoreactive processes and CBF neurons and evaluate whether these processes hypertrophy in AD patients. We observed by confocal laser microscopy a hyperinnervation of GAL-containing fibers in both AD and Parkinson's disease patients with concurrent AD (PD/AD). Galaninergic fibers were often seen in direct apposition to remaining CBF neurons and enwrapped cholinergic cell soma and dendrites. Our results demonstrate that GAL-containing fibers are in direct apposition to CBF neurons in normal-aged humans and that this phenotype is enhanced in AD and PD/AD, suggesting that direct synaptic contacts occur between GAL-containing fibers and CBF neurons. Because GAL can modulate acetylcholine release from cholinergic neurons, hyperinnervation of GAL fibers in AD and PD/AD patients may further decrease release of acetylcholine from remaining CBF neurons. We propose that therapies based solely on acetylcholinesterase inhibitors may be insufficient to effectively increase cortical levels of acetylcholine.
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PMID:A confocal microscopic analysis of galaninergic hyperinnervation of cholinergic basal forebrain neurons in Alzheimer's disease. 916 23


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