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)

Glutamic acid and its analogs are excitotoxins that might contribute to the pathogenesis of Parkinson's disease (PD). We measured four subtypes of glutamate binding sites autoradiographically in 20-microns sections from control and PD midbrains. N-Methyl-D-aspartate (NMDA) binding sites (eight control, eight PD) were very low in control (20 +/- 7 [SEM] fmol/mg protein) and were reduced in the PD pars compacta (2.6 +/- 1.1 fmol/mg protein; p less than 0.02). NMDA binding was also reduced in the red nucleus but not in periaqueductal gray (PAG). We measured alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), metabotropic, and non-NMDA, nonkainate, non-quisqualate (NNKQ) sites in 10 PD and 12 control midbrains. AMPA binding sites were reduced from 175 +/- 20 to 99 +/- 16 (p less than 0.05) fmol/mg protein in PD pars compacta, NNKQ sites from 86 +/- 10 to 50 +/- 12 (p less than 0.05) fmol/mg protein in total nigra, and metabotropic sites (15 +/- 5 fmol/mg protein) were unchanged. AMPA, metabotropic, and NNKQ binding were unchanged in red nucleus and PAG. The very low number of NMDA binding sites suggests that factors other than excitotoxicity mediated via NMDA receptors on nigral cell bodies play roles in the pathogenesis of PD. There may be a generalized loss of NMDA receptors in PD brains. AMPA and NNKQ binding sites appear to be located on dopamine neurons, although the role of NNKQ sites in normal nervous system function and human disease is unknown.
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PMID:Glutamate receptors in the substantia nigra of Parkinson's disease brains. 134 48

The capacity of the spinal cord of the rat to synthesize and metabolize catecholamines from injected L-DOPA, was tested at 10 and 100 days after a middle thoracic transection of the cord. There was no indication of even a minimal recovery of the capacity to synthesize noradrenaline in the caudal region of the transected cord. At 10 days after transection, the lumbar cord could synthesize 50% of the dopamine formed in the intact cord. At 100 days after transection the synthesis of dopamine in the transected cord was equal to that in the intact control animal. At both 10 and 100 days after transection, the dopamine synthesized from L-DOPA was efficiently metabolized to dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). As judged from the levels of gamma-aminobutyric acid (GABA) and glutamic acid (glutamate) present in the transected cord, no major metabolic derangement of the spinal cord tissue seemed to have been present at the times the experiments were done. It is concluded that dopamine can be efficiently synthesized and metabolized from its immediate precursor, L-DOPA, even in the absence of monoaminergic nerves. The results are discussed with reference to two main themes. The first, is the likelihood that in the therapeutic use of L-DOPA in states of chronic dopaminergic nerve degeneration (e.g. Parkinson's disease), the synthesis and metabolism of dopamine probably occurs throughout the entire central nervous system. The second, is the possible usefulness of L-DOPA to test for the relative intactness of spinal reflex circuities in the chronically spinalized animal.
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PMID:The synthesis and metabolism of catecholamines in the spinal cord of the rat after acute and chronic transections. 286 84

We measured the concentration of gamma-aminobutyric acid (GABA), glutamic acid, and o-phosphoethanolamine in autopsied brain of 9 patients who died with idiopathic Parkinson's disease and 10 control subjects. In the control striatum GABA showed an uneven rostrocaudal distribution pattern with rostral subdivisions containing about 40 to 50% higher levels. When compared with controls, GABA concentrations in Parkinson's disease striatum were generally elevated. The GABA elevation was most pronounced in the caudal subdivision of the putamen; this striatal subdivision also showed the most severe dopamine loss. We observed in the caudal putamen a significant negative correlation between the (elevated) GABA and (reduced) dopamine levels (the latter expressed as the sum of dopamine plus 3-methoxytyramine). Milder nonsignificant elevations of GABA levels were observed in intermediate and rostral putamen followed by the caudate head subdivisions. GABA levels were normal in all extrastriatal brain areas examined. Striatal glutamic acid levels were markedly elevated in 3 of the 9 patients with Parkinson's disease. We suggest that the altered GABA metabolism in the striatum, especially the putamen, is consequent to the nigrostriatal deficiency in this disorder. This secondary change in striatal GABA function is likely to contribute to the basal ganglia dysfunction produced by the striatal dopamine loss and thus may be related to certain aspects of parkinsonian symptomatology.
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PMID:Elevated gamma-aminobutyric acid level in striatal but not extrastriatal brain regions in Parkinson's disease: correlation with striatal dopamine loss. 287 65

We measured amino acid contents in autopsied brains of seven patients with progressive supranuclear palsy (PSP) and in control subjects dying without brain disease. Glutathione was also quantitated in rapidly frozen brains of PSP patients, Parkinson's disease (PD) patients, and controls. In PSP, we found glutamic acid markedly increased in the nucleus accumbens; taurine significantly increased in nucleus accumbens, substantia nigra, and globus pallidus; and gamma-aminobutyric acid significantly increased in nucleus accumbens and putamen. Glycerophosphoethanolamine contents were significantly increased in most regions. Glutathione, which is significantly decreased in substantia nigra in PD, was increased in this brain region in PSP, suggesting that different mechanisms may be responsible for destruction of dopaminergic nigrostriatal neurons in these two disorders.
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PMID:Brain amino acids and glutathione in progressive supranuclear palsy. 336 77

The incorporation of labelled carbon from glucose U-14C into CSF amino acids was investigated in three patients with Parkinson's disease and in three control persons with comparable age and physical stature. Comparing the specific radioactivities of serum and CSF one can postulate that the labelled amino acids found in the CSF are synthesized mainly by brain tissue. The resorption of glucose into the CNS and therefore the synthesis of amino acids from glucose was more rapid in controls; labelled alanine and glutamine appeared later in the CSF of the patients. As expected, in the controls the specific radioactivity of glutamic acid was found to be higher than that of glutamine, in patients the labelling of glutamine was higher as was that of serine, glycine, aspartic acid and asparagine. From our knowledge concerning the compartmentation of the metabolism of glutamate, we assume that in Parkinsonism the metabolic activity of neurons is reduced but that of astroglia is enhanced.
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PMID:[Biosynthesis of amino acids from glucose in the central nervous system in the Parkinson syndrome]. 665 3

This review describes recent advances in our understanding of the pharmacology of excitatory amino acid receptors, and the application of this knowledge to the unravelling of the aetiology of neurodegenerative diseases, and to their therapy. Ionotropic excitatory amino acid receptors can be divided into two large families, the NMDA receptor family, and the AMPA/kainate receptor family. Receptor cloning studies have shown there to be a large number of potential subtypes of receptors in both these families. Antagonists have been developed for the NMDA receptor which can interact with at least four independent drug recognition sites on the receptor. For the AMPA/kainate receptor, two classes of antagonist have so far been identified. Reasonably potent, selective and brain-penetrating antagonists now exist for virtually all these sites, and compounds inhibiting the release of glutamic acid presynaptically have also been identified, such as riluzole. The ability of glutamic acid to kill neurons (excitotoxicity) seems to be mediated, in most cases, by an interaction with NMDA receptors, leading to an uncontrollable rise in intracellular calcium concentrations and thence cell lysis and death. The setting-up of glutamatergic loops seems to be a key process in the maintenance, spread and amplification of neurodegenerative foci. The existence of such processes has been amply demonstrated in animal models of stroke, in which both NMDA and AMPA/kainate receptor antagonists have neuroprotective effects. Clinical trials are underway with NMDA receptor antagonists in stroke. Excitotoxic mechanisms probably also contribute to pathology in head trauma and viral encephalopathy. Ingestion of excitatory amino acids may play a role in neurological conditions of dietary aetiology, such as neurolathyrism and domoic acid intoxication. For chronic neurodegenerative diseases, the role of excitatory amino acids is much less clear, although there is some evidence for the existence of excitotoxic mechanisms in amyotrophic lateral sclerosis. Evidence from animal models suggests that drugs that block glutamatergic neurotransmission might be beneficial in Parkinson's disease, Huntington's chorea and amyotrophic lateral sclerosis, but the relevance of these animal models to the human pathology is not clear. However, preliminary clinical results suggest riluzole to be efficacious in prolonging survival in amyotrophic lateral sclerosis, and certain weak NMDA receptor antagonists are currently used in the treatment of Parkinson's disease. The next few years could witness a breakthrough in the treatment of neurological conditions as drugs that interfere with glutamatergic transmission become available for clinical use.
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PMID:Excitatory amino acid receptors and neurodegeneration. 748 87

Determinations of biopterin (BP), homovanilic acid (HVA), glutamic acid (GTA), and glutamine (GT) levels in cerebrospinal fluid (CSF) obtained through a lumbar tap were performed in 20 parkinsonian patients in different stages of evolution and without medication. In patients with motor symptoms not related to Parkinson's disease (dystonia, dyskinesia and essential tremor) (n = 4). In 7 other neurological patients subjected to spinal tap for diagnostic procedures neurotransmitters were also determined and taken as control groups. In 14 of the patients with Parkinson's disease, the symptoms were evaluated using conventional scales (UPDS, NYPDS, NWPDS, Schwab and England, and Hoehn and Yahr scale). The amplitude and the frequency of tremor were quantitatively evaluated through a single plane accelerometer Grass SP-1, akinesia was measured through reaction time to auditory stimuli, and rigidity through the speed of lineal movement. Evaluations were performed with the patient not on any medication for 1 week and repeated 1 h after the intake of 250 mg of 200/50 L-dopa/carbidopa preparation (Sinemet) and on a different day after the intake of biperiden (Akineton) 6 mg/day. Differences in neurotransmitter or metabolites levels between Parkinson's disease and control groups were determined through an independent Student's t test. Correlation between severity of symptoms in the scales and for each individual symptom measured through the quantitative tests and the levels of neurotransmitters in CSF were evaluated through the Pearson correlation analysis test. Modifications in the motor performance after administration of Sinemet and Akineton, and the levels of neurotransmitters were indirectly determined. RESULTS. (1) There were significant differences between the levels of BP and GT in patients with Parkinson's disease and control groups, (2) lower GTA levels correlated with more severe rigidity and akinesia, and with the best response to the administration of L-dopa and may be an important marker for prognosis, and (3) lower levels of GT correlated with least akinesia, but not with tremor, which may indicate that the akinesia depends on other biochemical abnormalities besides dopamine depletion.
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PMID:Neurotransmitter levels in cerebrospinal fluid in relation to severity of symptoms and response to medical therapy in Parkinson's disease. 763 Oct 94

This paper reviews the changes in dopaminergic, cholinergic and glutamatergic neurotransmission, which occur in the aging of the central nervous system (CNS) and in age-related diseases: Parkinson's disease (PD) and Alzheimer's disease (AD). Dopaminergic neurotransmission is impaired with age due to degeneration of the substantia nigra pars compacta neurons and reduction of the density of postsynaptic D1 and D2 dopamine receptors in the striatum. PD is believed to be caused by a severe loss of dopaminergic neurons, which leads to nearly complete depletion of dopamine in the striatum, particularly in the putamen. The supersensitivity of postsynaptic dopamine receptors, reported by some authors, may result from compensatory mechanisms to degeneration of dopaminergic neurons. The role of aging in PD is also discussed in the paper. An interest in the role of the cholinergic and glutamatergic systems in aging results from the concept that the development of AD is due to the pathology of these systems. The data on cholinergic neurotransmission are controversial and imply that aging affects rather slightly both neurons and cholinergic receptors. In AD, however, severe degeneration of cholinergic neurons of the basal nucleus of Meynert, leading to the impairment of cholinergic neurotransmission in the hippocampus and the cerebral cortex, has been observed. In AD degeneration of glutamatergic neurons and subsensitivity of some excitatory amino acids receptors in the hippocampus and the cerebral cortex may lead to dementia. However, an increase in the glutamate release from presynaptic glutamatergic terminals may be responsible for neuronal degeneration in AD. The role of the beta-amyloid protein in a neurodegenerative activity of glutamic acid is discussed.
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PMID:Disturbances in neurotransmission processes in aging and age-related diseases. 840 65

There have been many claims that the selective monoamine oxidase type B (MAO-B) inhibitor selegiline may have distinct properties in slowing the progression of Parkinson's disease (PD). Degeneration of nigro-striatal dopaminergic neurons is the primary histopathological feature of PD. Although many different hypotheses have been advanced, the cause of chronic nigral cell death and the underlying mechanisms remain elusive as yet. Therefore, there is no clear knowledge regarding an understanding of the reported effects of selegiline on the progression of PD. However, there is a considerable body of indirect evidence that oxidative stress may play a role in the pathogenesis of this illness. Oxidative stress refers to cytotoxic consequences of hydrogen peroxide and oxygen-derived free radicals such as the hydroxyl radical (.OH), the superoxide anion (.O2), and nitric oxide (NO), which are generated as byproducts of normal and aberrant metabolic processes that utilize molecular oxygen. On the other hand, an increasing body of experimental data has implicated excitotoxicity as a mechanism of cell death in both acute and chronic neurological disease. One of the receptor which is particularly involved in the toxic effects of excitatory amino acids is the NMDA (N-methyl-D-aspartate) receptor. Excessive stimulation of this type of receptor by glutamic acid or NMDA agonists leads to a massive influx of calcium ions into the neuron followed by activation of a variety of calcium-dependent enzymes, impaired mitochondrial function, and the generation of free radicals. This article will consider the concept that excitotoxicity is linked with the generation of free radicals. In view of this idea it will be further discussed how selegiline might exert its neuroprotective effects via indirect actions on the polyamine binding site of the NMDA receptor. Under treatment with the MAO-B inhibitor selegiline, the degradation of putrescine via MAO, a key factor in regulating the polyamine metabolism, might be diminished in the Parkinsonian brain, which in turn would suppress the polyamine synthesis. Hence, the reported neuroprotective effect of selegiline might also receive a contribution from the diminished potentiation of the NMDA receptor by the polyamine binding site. On the other hand, since N1-acetylated spermine and spermidine are also good substrates of MAO-B, it is likely that these compounds will be present in the brain in increased concentrations. It therefore seems possible that they will exert a neuroprotective effect via an antagonistic modulation of the polyamine binding site of the NMDA receptor.
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PMID:New horizons in molecular mechanisms underlying Parkinson's disease and in our understanding of the neuroprotective effects of selegiline. 898 58

Rats were treated intraperitoneally with a mixture of 250 mg/kg L-DOPA and 40 mg/kg carbidopa or with vehicle and sacrificed 30 min later. Plasma, heart and cortex, midbrain, brainstem and cerebellum were removed from each animal and assayed by HPLC for L-DOPA and a large number of amino acids and related amino compounds. L-DOPA levels increased from undetectable (<0.2 nmol/ml or g) to 1,146, 1,007, 399, 376, 368 and 850 nmol/ml or g in the above tissues. In addition, several amino compounds were significantly affected by L-DOPA/carbidopa (p < or = 0.01). Plasma concentrations of phosphoserine, oxidized glutathione, citrulline, phenylalanine, tyrosine and 1-methylhistidine increased and arginine, glutamic acid and lysine decreased. In the heart, concentrations of phosphoserine, taurine, reduced glutathione, threonine, serine, glutamine, glycine, alanine, valine, GABA, ethanolamine, ammonia and arginine decreased. In the cortex, camosine and homocarnosine increased. In the midbrain, valine increased and leucine, ornithine and oxidized glutathione decreased. In the cerebellum, citrulline increased. In the brainstem, threonine, serine, asparagine, glutamine, oxidized glutathione, alanine, and leucine decreased. In the brainstem, arginine was slightly decreased with a concomitant increase in citrulline (p < 0.05), indicative of nitrous oxide formation. These results show that administration of L-DOPA/ carbidopa not only raises dopamine levels but can also affect other biochemicals and that the observed changes in amino acids and related compounds can perhaps contribute to the beneficial and/or adverse effects of L-DOPA/carbidopa therapy of Parkinson's disease.
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PMID:Effects of L-DOPA/carbidopa administration on the levels of L-DOPA, other amino acids and related compounds in the plasma, brain and heart of the rat. 934 99


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