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

Quantitative receptor autoradiography using [3H]MK-801, [3H]glycine, [3H]CNQX and [3H]kainate was employed to determine the distribution and density of excitatory amino acid (EAA) binding sites in the midbrain and basal ganglia of the normal human nervous system. Detailed knowledge of the anatomy and subtype specificity of glutamate receptors is important both in understanding the normal physiology of basal ganglia neurotransmission and the pathophysiological changes occurring in diseases affecting the basal ganglia such as Parkinson's disease (PD). In PD, glutamate receptor activation may contribute to cell death of dopaminergic neurones in the substantia nigra. In addition, perturbation of glutamate neurotransmission resulting from dopamine depletion in the basal ganglia is likely to contribute to the clinical manifestations of motor dysfunction. The distribution and density of ligand binding representing N-methyl-D-aspartate (NMDA), AMPA (2-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) and kainate receptors has a heterogeneous distribution in the human midbrain and basal ganglia. In the substantia nigra relatively high densities of [3H]MK-801 and strychnine-insensitive [3H]glycine binding sites representing NMDA receptors were present, whereas only moderate densities of [3H]CNQX and [3H]kainate binding sites were present, compared to other regions. In both the medial globus pallidus and subthalamic nucleus, binding sites representing NMDA, AMPA and kainate receptors were all present at low density. These findings suggest that the clinical usefulness of modifying glutamatergic neurotransmission in these basal ganglia nuclei may be limited by the relatively low density of EAA binding sites present.
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PMID:The distribution of excitatory amino acid receptors in the normal human midbrain and basal ganglia with implications for Parkinson's disease: a quantitative autoradiographic study using [3H]MK-801, [3H]glycine, [3H]CNQX and [3H]kainate. 783 43

Excitatory amino acid receptor antagonists have been proposed as novel therapeutic agents to be used with levopoda in the treatment of Parkinson's disease. We examined the neural substrates for the interaction between levodopa and antagonists of either the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid or N-methyl-D-aspartate type of excitatory amino acid receptor using 2-deoxyglucose autoradiography. Thus, we compared the effects of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (10 mg/kg, i.v.) and the N-methyl-D-aspartate antagonist MK-801 (0.1 mg/kg, i.v.) on cerebral metabolic responses to levodopa (25 mg/kg, i.v., with 12.5 mg/kg benserazide) in rats with a unilateral nigrostriatal pathway lesion. Levodopa increased glucose utilization ipsilateral to the lesion in substantia nigra pars reticula (up to 104%), entopeduncular nucleus (up 90%) and subthalamic nucleus (up 30%), indicating that levodopa alters striatal output through the striatonigral, striatoentopeduncular and striatopallidal pathways. Levodopa also decreased metabolic rate in lateral habenula (down 39%), a target of projections from entopeduncular nucleus, implying a reduction in basal ganglia output. 2,3-Dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline and MK-801 by themselves did not affect glucose utilization in any of these regions. Pretreatment with 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline reduced the effect of levodopa in substantia nigra pars reticulata but not in entopeduncular nucleus or subthalamic nucleus, while MK-801 attenuated the effect of levodopa in all three of these structures; neither 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline nor MK-801 altered the effect of levodopa in lateral habenula. When given at the same doses to a separate group of lesioned animals, neither 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline nor MK-801 affected rotational behavior elicited by levodopa. These findings indicate that alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid and N-methyl-D-aspartate receptor antagonists differentially modify dopamine receptor-mediated striatal output. alpha-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor blockade may preferentially attenuate the effect of dopamine receptor activation on the striatonigral pathway, while N-methyl-D-aspartate blockade appears to reduce the actions of dopamine on the striatonigral, striatoentopeduncular and striatopallidal pathways.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Excitatory amino acid receptor antagonists modify regional cerebral metabolic responses to levodopa in 6-hydroxydopamine-lesioned rats. 800 98

Excitatory amino acid antagonists have been proposed as novel therapeutic agents for Parkinson's disease due to their ability to reverse akinesia in animal models of this disorder. To further evaluate this therapeutic potential, we examined the effects of a N-methyl-D-aspartate (NMDA) and an alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor antagonist on catalepsy produced by dopamine D1 or D2 receptor antagonists in rats. Male Sprague-Dawley rats were injected with dizocilpine (MK-801 0.025, 0.05 or 0.1 mg/kg i.p.), 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX 12.5 mg/kg i.p.) or saline prior to administration of either raclopride (2.5 mg/kg i.p.) or SCH 23390 (0.5 mg/kg i.p.). Catalepsy was evaluated with both grid and bar tests every 20 min for 2.7 h. MK-801 (0.1 mg/kg) reversed the catalepsy produced by either raclopride or SCH 23390 but did not stimulate locomotion when given alone at this dose. At 0.05 mg/kg, MK-801 markedly decreased SCH 23390-induced catalepsy, but did not affect the catalepsy produced by raclopride. In contrast, NBQX increased raclopride-induced catalepsy, but had no effect on catalepsy elicited by SCH 23390. These findings suggest that blockade of NMDA receptors, but not non-NMDA receptors, may reverse the catalepsy produced by dopamine receptor antagonists.
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PMID:Opposite effects of NMDA and AMPA receptor blockade on catalepsy induced by dopamine receptor antagonists. 838 18

It was shown in the present study that three antagonists of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) glutamate receptor, including 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline (NBQX), 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI 52466) and 6-(1H-imidazole-1-yl)-7-nitro-2,3-(1H, 4H)-quinoxalinedione (YM90K), caused marked reversal of akinesia when administered into the entopeduncular nucleus of rats rendered parkinsonian by bilateral substantia nigra pars compacta lesion. These data suggest that centrally active AMPA antagonists may have therapeutic utility in the treatment of idiopathic Parkinson's disease.
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PMID:Centrally-administered AMPA antagonists increase locomotion in parkinsonian rats. 852 99

Glutamate is one of the major excitatory neurotransmitter in the central nervous system. Glutamate acts on 4 different post synaptic receptors; NMDA (N-Methyl-D-aspartate) AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid), Kainate and metabotropic receptors. The three former receptors are linked to membrane ion channels whereas metabotropic receptors are coupled with a G protein. Glutamate is involved in the physiologic processes of learning, memory and motricity. Glutamate is also a potent neurotoxin responsible for toxic neuronal death of post synaptic neurons. This action has been denominated excitotoxicity and occurs as a consequence of a prolonged or a strong activation of glutamate post-synaptic receptors. The rise in intracellular calcium seems to play a major role in the pathological events following excitotoxicity. The pathophysiology of several acute or chronic neurological disorders has been linked to excitotoxicity. This excitotoxic process could be present in acute neuronal death observed in stroke, hypoglycemia and traumatisms of the central nervous system and in chronic neuronal degeneration observed in Amyotrophic Lateral Sclerosis (ALS), Alzheimer's disease, Parkinson's disease, Huntington's disease and neuro AIDS. A better knowledge of the cellular events induced by excitotoxicity will allow to consider new therapeutic approaches in various neurological disorders.
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PMID:[Role of glutamate and excitotoxicity in neurologic diseases]. 876 52

Using the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease, we investigated the long-term effects of dopaminergic denervation on synaptic transmission in an in vitro slice preparation of the mouse neostriatum. In control mice, electrical stimulation elicited an antidromic potential (N1) followed by a synaptically mediated field potential (N2). In many slices, a third component (N3) was observed. Determination of the maximum stimulus intensities unveiled that in 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine-pretreated animals, the stimulus strength necessary to evoke a maximum N2 response was significantly higher compared to control mice. Furthermore, 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine-pretreatment led to a less frequent appearance and/or to a reduction in the amplitude of the N3 component. Application of glutamate receptor agonists and antagonists revealed two additional differences between normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-pretreated mice. (1) Comparison of the efficacy of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist 6-cyano-7-nitroquinoxaline-2, 3-dione demonstrated an increase in the inhibitory effect of 6-cyano-7-nitroquinoxaline-2,3-dione in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-pretreated mice. (2) In normal mice, removal of magnesium ions from the bathing solution invariably led to the appearance of late N-methyl-D-aspartate receptor-dependent synaptic components. There components were only slightly expressed or virtually absent in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-pretreated mice. The described differences between the electrophysiological and pharmacological properties of evoked field potentials in slices from normal and 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine-pretreated mice disappeared following blockade of GABAA receptor-dependent inhibition by bicuculline. In normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-pretreated mice, bicuculline did not influence the amplitude of the N2 component, but invariably unmasked late synaptic components mediated by glutamate receptors. However, the potentiating effect of bicuculline was significantly stronger in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-pretreated mice compared to the controls. In the presence of bicuculline, the frequency of occurrence of the N3 component was identical in both groups. Furthermore, the apparent efficiency of 6-cyano-7-nitroquinoxaline-2,3-dione was no longer different. Application of bicuculline in the absence of magnesium ions resulted in a similar disinhibition of N-methyl-D-aspartate receptor-dependent late components as observed in the controls in the absence of bicuculline. The data demonstrate that chronic dopaminergic denervation reduces glutamate receptor-dependent synaptic excitation in the mouse neostriatum. Since differences between normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-pretreated mice disappear in the presence of bicuculline, we conclude that this reduction in excitability is due to a potentiation of GABAA receptor-dependent inhibition.
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PMID:1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic denervation potentiates gabaergic inhibition in the mouse neostriatum in vitro. 886 41

Parkinson's disease (PD) is characterized by the destruction of dopaminergic cells in the substantia nigra (SN). The cause of the cell death and the development of Parkinsonism is however unknown. There are increasing evidences to suggest the involvement of glutamate mediated by its receptors. Using immunohistochemistry and cell counting, the present study investigated whether the numbers of neurons immunostained with glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor subunits GluR1, GluR2/3 and GluR4 in the SN of rats would change after the injection of 6-hydroxydopamine (6-OHDA) into the SN. The results showed that the numbers of GluR1 positive cells were significantly decreased in the substantia nigra pars compacta (SNc), pars reticulata (SNr) and pars lateralis (SNl) from 3 days (13.7%) to 3 months (40.3%) and of GluR2/3 cells, from 1 week (17.6%) to 3 months (19.1%) after 6-OHDA injection, compared to those in the contralateral non-injected side. There was, however, no significant difference in the number of GluR4 positive cells between the injected and non-injected SN. The results were discussed.
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PMID:Effect of 6-OHDA injection on the AMPA glutamate receptor subunits in the substantia nigra of Sprague-Dawley rats. 950 1

Glutamatergic neurotransmission in the substantia nigra pars compacta and pars reticulata is mediated through N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methyl-4-isoxaline propionic acid/kainate (AMPA) type receptors as well as other glutamate receptors and is critical for basal ganglia functioning. A major glutamatergic input to the substantia nigra originates in the subthalamic nucleus, and the long-lasting stimulation of the dopaminergic cells of the substantia nigra pars compacta by the subthalamic neurons has been implicated in the pathophysiology of Parkinson's disease. The objectives of the present study were to determine the subcellular and subsynaptic localization of subunits of the N-methyl-D-aspartate and AMPA receptors in the substantia nigra, and also to determine whether co-localization of N-methyl-D-aspartate and AMPA receptor subunits occur at individual synapses. To achieve this, pre-embedding and post-embedding immunocytochemistry was applied to sections of substantia nigra using antibodies that recognize the NR1 and NR2A/B subunits of the N-methyl-D-aspartate receptor, and GluR2/3 subunits of the AMPA receptor. In both regions of the substantia nigra, immunolabelling for each of the subunits was observed in numerous perikarya and proximal dendrites. At the subcellular level, silver-intensified immunogold particles localizing N-methyl-D-aspartate and AMPA receptor subunits were most commonly present within dendrites where they were associated with a variety of intracellular organelles and with the internal surface of the plasma membrane. Post-embedding immunogold labelling revealed immunoparticles labelling for NR1, NR2A/B and GluR2/3 to be enriched at asymmetric synaptic specializations, although a large proportion of asymmetric synapses were immunonegative. Double immunolabelling revealed, in addition to single-labelled synapses, the co-localization of subunits of the N-methyl-D-aspartate receptor and subunits of the AMPA receptor at individual asymmetric synapses. Similarly, double immunolabelling also revealed the co-localization of the NRl and NR2A/B subunits of the N-methyl-D-aspartate receptor at individual asymmetric synapses. Labelling for NR1 and GluR2/3 was, on average, relatively evenly distributed across the width of the synapse with a gradual reduction towards the periphery when analysed in single sections. In summary, the present results demonstrate that AMPA and N-methyl-D-aspartate receptors are selectively localized at a subpopulation of asymmetric synapses in the substantia nigra pars compacta and reticulata and that the two receptor types, at least partially co-localize at individual synapses. It is concluded that glutamatergic transmission in the substantia nigra pars compacta and pars reticulata occurs primarily at asymmetric synapses and, at least in part, is mediated by both N-methyl-D-aspartate and AMPA receptors.
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PMID:Synaptic localization of ionotropic glutamate receptors in the rat substantia nigra. 1111 53

Although the presence of an olfactory impairment in Parkinson's disease (PD) has been recognized for 25 years, its cause remains unclear. Here we suggest a contributing factor to this impairment, namely, that PD impairs active sniffing of odorants. We tested 10 men and 10 women with clinically typical PD, and 20 age- and gender-matched healthy controls, in four olfactory tasks: (i) the University of Pennsylvania smell identification test; (ii and iii) detection threshold tests for the odorants vanillin and propionic acid; and (iv) a two-alternative forced-choice detection paradigm during which sniff parameters (airflow peak rate, mean rate, volume, and duration) were recorded with a pneomatotachograph-coupled spirometer. An additional experiment tested the effect of intentionally increasing sniff vigor on olfactory performance in 20 additional patients. PD patients were significantly impaired in olfactory identification (P < 0.0001) and detection (P < 0.007). As predicted, PD patients were also significantly impaired at sniffing, demonstrating significantly reduced sniff airflow rate (P < 0.01) and volume (P < 0.002). Furthermore, a patient's ability to sniff predicted his or her performance on olfactory tasks, i.e., the more poorly patients sniffed, the worse their performance on olfaction tests (P < 0.009). Finally, increasing sniff vigor improved olfactory performance in those patients whose baseline performance had been poorest (P < 0.05). These findings implicate a sniffing impairment as a component of the olfactory impairment in PD and further depict sniffing as an important component of human olfaction.
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PMID:An impairment in sniffing contributes to the olfactory impairment in Parkinson's disease. 1125 73


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