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The partial dopamine receptor agonist terguride in the MPTP-induced hemiparkinsonian monkey model
T Brücke1, K Bankiewicz, J Harvey-White
1National Institutes of Health, Bethesda, MD 20892.
Abstract:
The partial dopamine agonist terguride (transdihydrolisuride) administered to four 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesioned hemiparkinsonian monkeys (at a dose of 4 mg/kg orally) induced marked contralateral turning that lasted 3.5 h. The 6-n-propyl derivative of terguride (proterguride) given to two monkeys (at a dose of 0.4 mg/kg orally) caused contralateral turning which lasted for more than 24 h but produced side effects such as dyskinesia and stereotype. After terguride treatment, cerebrospinal fluid concentrations of 3-methoxy-4-hydroxy-phenylglycol (MHPG) were increased, whereas concentrations of the metabolites dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) were not significantly altered.
Insights
Terguride and proterguride, dopamine agonists, were tested in MPTP-lesioned parkinsonian monkeys. Proterguride showed prolonged effects but caused side effects, indicating potential therapeutic differences.
Area of Science:
- Neuroscience
- Pharmacology
- Primate Models
Background:
- Parkinson's disease is a neurodegenerative disorder characterized by dopamine deficiency.
- MPTP-induced hemiparkinsonism in non-human primates serves as a valuable model for studying Parkinson's disease.
- Dopamine agonists are a key therapeutic strategy for managing Parkinson's disease symptoms.
Purpose of the Study:
- To evaluate the efficacy and side effect profile of terguride and its derivative, proterguride, in a primate model of Parkinson's disease.
- To investigate the neurochemical effects of terguride treatment on dopamine and serotonin metabolites in cerebrospinal fluid.
Main Methods:
- Administration of terguride (4 mg/kg, orally) and proterguride (0.4 mg/kg, orally) to MPTP-lesioned hemiparkinsonian monkeys.
- Quantification of contralateral turning behavior as a measure of motor response.
- Analysis of cerebrospinal fluid (CSF) concentrations of neurotransmitter metabolites, including MHPG, DOPAC, HVA, and 5-HIAA.
Main Results:
- Terguride induced marked contralateral turning for 3.5 hours in MPTP-lesioned monkeys.
- Proterguride caused prolonged contralateral turning (>24 hours) but was associated with dyskinesia and stereotypy.
- Terguride treatment increased CSF concentrations of MHPG, while DOPAC, HVA, and 5-HIAA levels remained unchanged.
Conclusions:
- Terguride demonstrates partial dopamine agonist activity with a manageable duration of action in a primate Parkinson's model.
- Proterguride exhibits extended efficacy but is limited by significant side effects, suggesting a less favorable therapeutic window.
- The observed increase in MHPG following terguride treatment may indicate complex interactions within noradrenergic systems, warranting further investigation.