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)

Progress in Parkinson's disease research has been rapid in recent years from both a scientific and clinical point of view. The MPTP discovery represented a milestone in the knowledge of the biochemical mechanism underlying degeneration of dopaminergic neurons of the nigrostriatal pathway. Recent life and scientific events have initiated, even ironically, new trends in the mechanism of MPTP toxicity. The role of excitatory amino acids, particularly of NMDA receptors, in this toxicant-induced degenerative process, seems to be crucial. If this new finding is further confirmed by studies on primates, the animal species most sensitive to the neurotoxin, research into Parkinson's disease might move in other directions, useful in both treatment and prevention.
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PMID:In memoriam Richard Heikkila. The MPTP story: irony creeps back in. 177 76

Degeneration of dopaminergic nigrostriatal neurons in Parkinson's disease results in an overactivity of excitatory glutamatergic projections from the subthalamic nucleus to the output nuclei of the basal ganglia resulting in rigidity and akinesia. In theory pharmacological blockade of these overactive systems should improve parkinsonian symptomatology. The selective AMPA-antagonist NBQX and the competitive NMDA-antagonist CPP are not effective in animal models of Parkinson's disease when given alone but ameliorate parkinsonian symptomatology and stimulate locomotor activity when co-administered with a threshold dose of L-Dopa. These synergistic effects are seen in the MPTP-treated (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) common marmoset and the rat with unilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra. Therefore competitive NMDA and non-NMDA antagonists may offer a new therapeutic strategy for the treatment of Parkinson's disease.
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PMID:Synergism of the AMPA-antagonist NBQX and the NMDA-antagonist CPP with L-dopa in models of Parkinson's disease. 183 81

Recent data on the aptitude of adamantamines to inhibit or to stimulate glutamatergic (NMDA) neuromediation, to display anti-GABAergic and antiglycinergic components (by blocking the Cl- channel), on the one hand, and on the opposition of the central glutamatergic and dopaminergic systems, on the other, could suggest that the glutamatergic (NMDA) or the anti-NMDA activity, exhibited by some adamantamines, could play an important role in the expression of their pharmacological profile. Anti-NMDA properties, for the adamantamines which exhibited them, could be, by themselves or by developing their anti-GABAergic or antiglycinergic components, the first cause of the hypermotility and dopaminomimetic activity induced by these molecules. Glutamatergic (NMDA) component, which could be displayed by some lipophilic or important steric obstruction on azote exhibiting adamantamines, could amplifie the excitating effects of their anti-GABAergic and antiglycinergic components on the limbic system's brain structures (hippocampus, amygdala) and could contribute to the exhibition of hypomotility, fright, agressivity and convulsions. According to these data, which must be amplier confirmed and deeped, it would be possible to envisage the improvement of adamantamines against the Parkinson's disease (when they exhibit anti-NMDA activity) or their use against the Alzheimer's disease and the late stages of the Parkinson's disease (when they exhibit NMDA activity).
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PMID:[Action mechanism of adamantamines: do their activity on glutamatergic receptors intervene in the expression of their pharmacological profile?]. 184 25

Intake of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) leads to symptoms of Parkinson's disease and produces degeneration of nigrostriatal dopaminergic neurons in humans, giving rise to the hypothesis that this disorder may be caused by endogenous or environmental toxins. Excitation mediated by dicarboxylic amino acids such as L-glutamate or L-aspartate, has been claimed to be involved in pathogenesis of neurodegenerative disorders. We therefore sought to determine whether antagonists active at the NMDA or quisqualate subtypes of L-glutamate receptors prevent toxicity of either MPP+ (1-methyl-4-phenyl-pyridinium ion, the active metabolite of MPTP) or the selective dopaminergic neurotoxin 6-OHDA in the rat substantia nigra pars compacta. We report here that certain selective NMDA antagonists (AP7, CPP, MK-801), but not the preferential quisqualate antagonists CNQX and NBQX, provided short-term (up to 24 h) protection against MPP+ toxicity when coadministered into the substantia nigra. Systemic administration of CPP or MK-801 also offered temporary protection for up to 4 h against MPP+ toxicity. Repeated systemic administration of either compound prolonged protection against MPP+ challenge. Repeated administration for at least 24 h also led to permanent protection, still evident 7 days after intranigral administration of MPP+.
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PMID:Protection of substantia nigra from MPP+ neurotoxicity by N-methyl-D-aspartate antagonists. 183 Sep 25

The present study shows that high doses of the non-competitive NMDA antagonist phencyclidine (PCP) as well as of the competitive NMDA antagonist SDZ EAA494 (D-CPPene) increase locomotion in monoamine-depleted mice. The pattern of movement produced following treatment with these agents is very similar to that previously observed following MK-801 administration to monamine-depleted mice. When subthreshold doses of MK-801, PCP and SDZ EAA494 were combined with the alpha-adrenergic agonist clonidine, a dramatic stimulation of locomotion was observed in monoamine-depleted mice; the gross appearance of the animals was similar with the three drug combinations. These results support our previous conclusion that suppression of glutamatergic neurotransmission promotes the locomotor stimulatory potential of other (e.g. adrenergic) transmitter systems. The present findings may be of relevance for future treatment strategies in (L-DOPA-resistant) Parkinson's disease.
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PMID:The non-competitive NMDA antagonists MK-801 and PCP, as well as the competitive NMDA antagonist SDZ EAA494 (D-CPPene), interact synergistically with clonidine to promote locomotion in monoamine-depleted mice. 214 54

N-methyl-D-aspartic acid (NMDA; 40 mg/kg, i.p.) did not elicit catalepsy, but it potentiated the cataleptic effect of haloperidol and GABAB receptor agonist, baclofen. MK-801 (0.2 mg/kg, i.p.), NMDA-receptor antagonist, reversed haloperidol- but not baclofen-induced catalepsy. MK-801 also potentiated the anticataleptic effect of scopolamine and bromocriptine against haloperidol-induced catalepsy. Dihydropyridine (DHP) calcium-channel antagonists such as nimodipine and nitrendipine (10 mg/kg, i.p.), reversed the anticataleptic effect of MK-801, and potentiated the cataleptic effect of haloperidol, as well as baclofen. These observations indicate the involvement of NMDA receptors in catalepsy, and suggest a potential clinical implication of NMDA-receptor antagonists in Parkinson's disease.
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PMID:Role of N-methyl-D-aspartate (NMDA) receptors in experimental catalepsy in rats. 215 85

In the present paper it is shown that when either of the noncompetitive NMDA antagonists MK-801 or ketamine are combined with the alpha-adrenergic agonist clonidine, a pronounced stimulation of locomotion is produced in monoamine-depleted mice. Likewise, when a subthreshold dose of MK-801 is combined with the muscarinic antagonist atropine, a forceful synergism with regard to locomotor activity in monoamine-depleted mice is observed. Furthermore, the present study shows that also in monoamine-depleted rats MK-801, as well as the competitive NMDA antagonist AP-5 (DL-2-amino-5-phosphonovaleric acid), interact synergistically with clonidine to enhance locomotor activity. Taken together, our findings suggest that central glutamatergic systems exert a powerful inhibitory influence on locomotion. Interfering with this inhibitory force by administration of an NMDA antagonist promotes locomotion and discloses the activational potential of other transmitter systems. The results are discussed in relation to 1) the pathophysiology of schizophrenia, with emphasis on the glutamate hypothesis of schizophrenia, and 2) implications for the treatment of Parkinson's disease.
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PMID:Interfering with glutamatergic neurotransmission by means of NMDA antagonist administration discloses the locomotor stimulatory potential of other transmitter systems. 216 45

Current evidence suggests that the motor symptoms of parkinsonism are due to abnormal overactivity of the medial segment of the globus pallidus, brought about by overactivity of the subthalamic nucleus, from which it receives an excitatory amino acid-mediated projection. The possibility exits, therefore, that excitatory amino acid antagonists might have an anti-parkinson effect by normalising medial pallidal activity. The NMDA antagonist MK-801 was administered i.m. to a single cynomolgus monkey with parkinsonism induced by the neurotoxin MPTP. In fact, MK-801 exacerbated the symptoms of parkinsonism. When administered after a therapeutic dose of L-DOPA it antagonised the anti-parkinson action of L-DOPA. The results suggest that any potential anti-parkinson action of excitatory amino acid antagonists will depend upon an action at non-NMDA sites. The administration of the selective neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to produce a primate model of Parkinson's disease is well-documented (Burns, Markey, Phillips & Chiuch, 1984; Crossman, 1987; Langston, Forno, Rebert & Irwin, 1984). Intravenous injection of MPTP, titrated judiciously over a period of several weeks, can produce a stable manifestation of the motor disability seen in the idiopathic disease of man, with a remarkable correspondence of both symptoms and pathology. Additionally, primates rendered parkinsonian by MPTP respond well to L-DOPA treatment. As in human Parkinson's disease, long-term L-DOPA therapy of MPTP-induced parkinsonism tends to be complicated by the emergence of choreiform movements and dystonic postures (Boyce, Clarke, Luquin, Peggs, Robertson, Mitchell, Sambrook & Crossman, 1989; Clarke, Sambrook, Mitchell & Crossman, 1987).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of the NMDA antagonist MK-801 on MPTP-induced parkinsonism in the monkey. 268 16

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

NMDA and non-NMDA (AMPA/kainate) antagonists have potential in the treatment of a diverse group of neurological disorders associated with excessive activation of excitatory amino acid receptors. Here Michael Rogawski reviews recent progress in the development of therapeutically useful NMDA receptor channel blockers and a new class of selective AMPA/kainate receptor antagonists, the 2,3-benzodiazepines. Research on these novel noncompetitive excitatory amino acid antagonists has opened promising new avenues for the development of drugs to treat epilepsy, ischaemia, neurodegeneration and Parkinson's disease.
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PMID:Therapeutic potential of excitatory amino acid antagonists: channel blockers and 2,3-benzodiazepines. 750 60


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