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)

Parkinson's disease (PD) and Alzheimer's disease (AD) may share certain abnormalities since a subset of PD patients suffer from dementia, and some AD individuals show extrapyramidal symptoms. In vitro quantitative autoradiography was used to examine different subtypes of excitatory amino acid (EAA) receptors (NMDA, KA, and AMPA) and dopamine transporter sites in the striatum (caudate, putamen) and nucleus accumbens (NAc) from idiopathic PD, pure AD, and mixed PD/AD patients. PD and AD groups, and to a lesser extent the PD/AD groups, showed substantially increased binding to NMDA receptors in the striatum and NAc. No statistically significant changes in binding to KA and AMPA receptors were found in any patient group. 3H-mazindol binding to dopamine transporter sites was significantly decreased in the striatum and NAc of PD and PD/AD patients, but only in the putamen and NAc of AD patients. The data indicate that (1) the majority of striatal EAA receptors are not located on dopaminergic nigrostriatal nerve terminals, and (2) elevated binding to striatal NMDA receptors correlates with binding to dopamine transporter sites in PD patients, but not in AD and PD/AD individuals. Thus, the mechanisms of NMDA receptor changes in the striatum of AD and PD patients may be different. However, it is postulated that increased binding to NMDA receptors in Parkinson and Alzheimer striatum occurs in response to an insult(s) within the striatothalamocortical circuits and that this may contribute to the clinical similarities described for subsets of PD and AD patients.
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PMID:Selective increase of NMDA-sensitive glutamate binding in the striatum of Parkinson's disease, Alzheimer's disease, and mixed Parkinson's disease/Alzheimer's disease patients: an autoradiographic study. 796 38

Recent findings in monkeys indicate that excitatory amino acids such as glutamate are involved in the pathophysiological cascade of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)- induced neuronal cell death. The neuroprotective effects of competitive and non-competitive NMDA (N-methyl-D-aspartate) antagonists against MPTP toxicity support the hypothesis that NMDA receptor-mediated events are involved in the neurotoxicity of MPTP. These results suggest that the clinical trial of NMDA antagonists in patients with Parkinson's disease should be performed. Further evidence obtained in animal models of Parkinson's disease indicates that both competitive NMDA antagonists and AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate) antagonists show symptomatic anti-parkinsonian activity in combination with L-DOPA. Glutamate antagonists may therefore retard the progression and improve the symptomatology of Parkinson's disease. The 1-amino-adamantanes amantadine and memantine have recently been shown to be non-competitive NMDA antagonists and are widely used in Europe as anti-parkinsonian agents. Both compounds are likely to cause pharmacotoxic psychosis as an unwanted side-effect. Clinical trials are needed to test the efficacy of the 1-amino-adamantanes with respect to the progression of Parkinson's disease.
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PMID:Glutamatergic drugs in Parkinson's disease. 799 66

In rodent models of Parkinson's disease such as reserpinized or 6-hydroxydopamine substantia nigra lesioned rats, blockade of glutamate receptors of the NMDA (N-methyl-D-aspartate) or the AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate) receptor subtypes and concomitant treatment with L-DOPA (L-3,4-dihydroxyphenylalanine) or direct dopamine agonists restores locomotor activity and induces rotations. An alternative approach to interfere with glutamatergic transmission would involve the inhibition of glutamate release resulting in functional glutamate antagonism. The novel antiepileptic drug lamotrigine blocks the veratridine-evoked release of the excitatory transmitters L-glutamate and L-aspartate. Due to its presumed antiglutamatergic action it has been suggested that lamotrigine may be useful in the treatment of Parkinson's disease. In a preliminary open-label study in patients with Parkinson's disease some favourable effects were reported. The present study was undertaken to systematically investigate the effects of lamotrigine in rat models of Parkinson's disease. However, lamotrigine failed to exert antiparkinsonian activity in reserpinized rats when administered alone or in combination with the dopamine receptor agonist apomorphine. In rats bearing 6-hydroxydopamine lesions of the substantia nigra lamotrigine did not induce rotations when given alone and did not modify rotations induced by apomorphine or the preferential dopamine D2 receptor agonist lisuride. On the basis of these negative results it is predicted that lamotrigine will not have significant favourable effects on akinesia and rigidity in Parkinson's disease patients.
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PMID:Lamotrigine has no antiparkinsonian activity in rat models of Parkinson's disease. 854 15

Combinations of dopaminergic agonists with glutamate receptor antagonists have been suggested to be a possible alternative treatment of Parkinson's disease. To gain further insights into this possibility, the antagonist of the competitive AMPA-type glutamate receptor NBQX and the ion-channel blocker of the NMDA glutamate receptor (+)-MK-801 in combination with the dopamine D1 receptor agonists: SKF 38393, SKF 82958 and dihydrexidine; the dopamine D2 receptor agonist bromocriptine and the dopamine-precursor L-DOPA were tested in rats pretreated with reserpine and alpha-methyl-p-tyrosine. MK-801 on its own induced locomotor behaviour and potentiated the antiakinetic effects of dihydrexidine and L-DOPA but not of the other dopamine agonists tested. NBQX neither on its own nor coadministered with the dopamine agonists tested had an antiakinetic effect. These results indicate that agents, blocking the ion-channel of the NMDA receptor, might be useful adjuvants to some but not all dopaminomimetics in therapy of Parkinson's disease. The same does not seem to be true for the AMPA-antagonist NBQX.
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PMID:Effect of coadministration of glutamate receptor antagonists and dopaminergic agonists on locomotion in monoamine-depleted rats. 861 7

The 6-hydroxydopamine rat model of Parkinson's disease was combined with intracerebral drug infusions to examine the influence of glutamate receptors on striatal output activity. When infused into the dopamine-denervated striatum, the AMPA-kainate receptor antagonist DNQX dose-dependently elicited contralateral rotation and ipsilateral Fos immunoreactivity (Fos-IR) in the globus pallidus, a target nucleus of striatal output. DNQX did not elicit rotation or Fos-IR in unlesioned or partially lesioned rats. In addition, the NMDA receptor antagonist AP-5 failed to induce rotation and had minimal effects on pallidal Fos-IR in lesioned rats. These results suggest a role for striatal AMPA-kainate receptors in the pathology and treatment of Parkinson's disease.
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PMID:Intrastriatal DNQX induces rotation and pallidal Fos in the 6-OHDA model of Parkinson's disease. 874 70

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

The objective of the present study was to analyze the cellular and subcellular localization of ionotropic glutamate receptor subunits in midbrain dopaminergic neurons in the squirrel monkey. This was achieved by means of immunohistochemistry at light and electron microscopic levels and in situ hybridization histochemistry. Colocalization studies show that nearly all dopaminergic neurons in both the ventral and dorsal tiers of the substantia nigra compacta (SNc-v, SNc-d) and the ventral tegmental area (VTA) are immunoreactive for AMPA (GluR1, GluR2/3, and GluR4) and NMDAR1 receptor subunits, but not for NMDAR2A/B subunits. The immunoreactivity of the receptor subunits is associated mainly with perikarya and dendritic shafts. Apart from the intensity of immunolabeling for the GluR4 subunit, which is quite similar for the different groups of midbrain dopaminergic neurons, the overall intensity of immunostaining for the other subunits is higher in the SNc-v and SNc-d than in the VTA. In line with these observations, in situ hybridization shows that the average level of labeling for the GluR2 and NMDAR1 subunit mRNAs is significantly higher in the SNc-v than in the VTA, and for the NMDAR1 subunit, higher in the SNc-v than in the SNc-d. In contrast, no significant difference was found for the level of GluR1 mRNA labeling among the three groups of midbrain dopaminergic neurons. At the subcellular level in the SNc-v, AMPA (GluR1 and GluR2/3) and NMDAR1 receptor subunit immunoreactivity is preferentially associated with the postsynaptic densities of asymmetric synapses, but occasionally some immunoreactivity is found along nonsynaptic portions of plasma membranes of dendrites. A small number of preterminal axons, axon terminals, and glial cell processes are also immunoreactive. Our observations indicate that the different groups of midbrain dopaminergic neurons in primates exhibit a certain degree of heterogeneity with regard to the level of expression of some ionotropic glutamate receptor subunits. The widespread neuronal and glial localization of glutamate receptor subunits suggests that excitatory amino acids may act at different levels to control the basal activity and, possibly, to participate in the degeneration of midbrain dopaminergic neurons in Parkinson's disease.
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PMID:AMPA and NMDA glutamate receptor subunits in midbrain dopaminergic neurons in the squirrel monkey: an immunohistochemical and in situ hybridization study. 900 80

In parkinsonism, glutamate pathways within the basal ganglia become overactive, leading to the suggestion that glutamate antagonists might possess antiparkinsonian qualities. This report examines the motor properties of antagonists of NMDA and AMPA-type glutamate receptors, as well as some inhibitors of glutamate release, in animal models of idiopathic Parkinson's disease. High affinity NMDA open-channel blockers (e.g. MK 801, phencyclidine), are highly potent antagonists with inconsistent antiakinetic and strong myorelaxant activity. Other compounds are better tolerated and are capable of relieving immobility and muscular rigidity by themselves (e.g. 1-aminoadamantanes, polyamine site antagonists, kappa agonists, riluzole). Yet others do not restore movements alone (e.g. dextromethorphan, ketamine), but may interact with and strengthen the antiparkinsonian action of L-DOPA (e.g. competitive NMDA and AMPA antagonists, lamotrigine). They may do this by potentiating dopaminergic behaviours mediated by D1 or D2 receptors, or by some other mechanism.
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PMID:Stimulation of basal and L-DOPA-induced motor activity by glutamate antagonists in animal models of Parkinson's disease. 919 1

We have analyzed the serum from patients with refractory epilepsy for the presence of autoreactive antibodies to AMPA glutamate receptor subunits. The presence and the level of autoantibodies were assessed using immunoblot and ELISA with synthetic peptides specific for subregions of AMPA glutamate receptor subunits. Patients with refractory epilepsy exhibited strong immunoreactivity to GluR1 subunit compared to healthy donors and patients with Parkinson's disease and Alzheimer's disease. Weak immunoreactivity to other AMPA glutamate receptor subunits was also detected and the signal was diminished in the raw GluR4>GluR3>GluR2. The occurrence of autoantibodies to specific neurotransmitter subunits in the sera of patients with refractory epilepsy suggest that autoimmune process may underlie this disorder.
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PMID:The presence of autoantibodies to N-terminus domain of GluR1 subunit of AMPA receptor in the blood serum of patients with epilepsy. 939 30

This study examines the hypothesis that glutamate tonically suppresses the activity of the enzyme aromatic L-amino acid decarboxylase (AADC), and hence the biosynthesis of dopamine, to explain how antagonists of glutamate receptors might potentiale the motor actions of L-DOPA in animal models of Parkinson's disease. A variety of glutamate antagonists were therefore administered acutely to normal rats, which were sacrificed 30-60 min later and AADC activity assayed in the substantia nigra pars reticulata (SNr) and corpus striatum (CS). The NMDA receptor-ion channel antagonists MK 801, budipine, amantadine, memantine and dextromethorphan all caused a pronounced in creased in AADC activity, more especially in the SNr than CS. The NMDA glycine site antagonist (R)-HA 966 produced a modest increase in AADC activity in the CS but not SNr, whilst the NMDA polyamine site antagonist eliprodil, the NMDA competitive antagonist CGP 40116 and the AMPA antagonist NBQX were without effect. The results suggest that an increase in dopamine synthesis might contribute to the L-DOPA-facilitating actions of some glutamate antagonists.
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PMID:Effects of glutamate antagonists on the activity of aromatic L-amino acid decarboxylase. 987 40


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