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Effect of the NMDA antagonist MK-801 on MPTP-induced parkinsonism in the monkey
A R Crossman1, D Peggs, S Boyce
1Department of Cell and Structural Biology, Medical School, University of Manchester, U.K.
Abstract:
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)
Insights
Excitatory amino acid antagonists may offer anti-parkinsonian effects by targeting non-NMDA receptors. The NMDA antagonist MK-801 worsened parkinsonism symptoms in MPTP-treated monkeys, suggesting a need for different therapeutic targets.
Area of Science:
- Neuroscience
- Pharmacology
Background:
- Parkinsonism motor symptoms are linked to overactive medial globus pallidus due to subthalamic nucleus overactivity.
- Excitatory amino acid antagonists are hypothesized to treat parkinsonism by normalizing medial pallidal activity.
Purpose of the Study:
- To investigate the anti-parkinsonian effects of NMDA receptor antagonists.
- To evaluate the efficacy of MK-801 in a primate model of Parkinson's disease.
Main Methods:
- Induced parkinsonism in a cynomolgus monkey using N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).
- Administered the NMDA antagonist MK-801 intramuscularly.
- Assessed the effects of MK-801 alone and in combination with L-DOPA.
Main Results:
- MK-801 exacerbated parkinsonian motor symptoms.
- MK-801 antagonized the anti-parkinsonian effects of L-DOPA.
- The study suggests that non-NMDA receptor sites may be crucial for potential therapeutic actions.
Conclusions:
- NMDA receptor antagonism is not an effective strategy for treating MPTP-induced parkinsonism.
- Future research on excitatory amino acid antagonists should focus on non-NMDA receptor targets.
- Understanding receptor-specific actions is vital for developing novel Parkinson's disease therapies.