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MPTP, impairment of motor performance and amine accumulation in Macaca fascicularis
G L Willis1, J Savulescu, M K Horne
1Monash University, Department of Psychological Medicine, Prince Henry's Hospital, Melbourne, Victoria, Australia.
Abstract:
The selective neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was injected (IV) into monkeys (Macaca fascicularis) in two different injection regimes. With the small dose regime, one monkey was injected with 0.25 mg/kg, every other day, over a 16 day period. In the large dose regime, another monkey was injected with 0.5 mg/kg every other day, over an 8 day period. While the time required for drug delivery was varied between animals, the total dose delivered was 2 mg/kg in both animals. Before, during and for 14 days after the course of drug administration both animals were assessed on several motor function tests. The animal receiving the small dose regime showed normal motor performance on all tests for the duration of the study, however, the monkey receiving the large dose regime displayed progressive akinesia, muscular rigidity, and aphagia. In fact, impairment was so severe that this animal had to be force fed and maintained with daily oral L-dopa. Fluorescent histochemical assessment of forebrain in both monkeys revealed that striatal tissue was totally devoid of fluorescence in both cases. Large, swollen axons in the internal capsule, hypothalamus and midbrain were visible only in the severely impaired animal. These results suggest that, as with other neurotoxins, degeneration associated increases in amines may be important in the aetiology of Parkinson-like motor impairment produced by selective neurotoxins.
Insights
The neurotoxin MPTP caused Parkinson-like symptoms in monkeys at high doses, but not low doses. This suggests neurotoxin-induced amine changes may cause Parkinsonism.
Area of Science:
- Neuroscience
- Toxicology
- Primatology
Background:
- 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a selective neurotoxin.
- MPTP causes Parkinson-like symptoms in humans and animals.
- The precise mechanisms of MPTP neurotoxicity are not fully understood.
Purpose of the Study:
- To investigate the effects of different MPTP injection regimes on motor function and neurochemistry in Macaca fascicularis monkeys.
- To determine the dose-dependent neurotoxic effects of MPTP.
- To explore the relationship between MPTP-induced neurodegeneration and Parkinson-like motor impairments.
Main Methods:
- Two groups of Macaca fascicularis monkeys were administered MPTP via intravenous injection using distinct dose regimes (small vs. large).
- Motor function was assessed using standardized tests before, during, and after MPTP administration.
- Forebrain tissue was analyzed using fluorescent histochemistry to examine neurochemical changes and axonal degeneration.
Main Results:
- Monkeys receiving the large dose regime exhibited progressive akinesia, muscular rigidity, and aphagia, requiring force feeding and L-dopa treatment.
- The monkey in the small dose regime showed normal motor performance throughout the study.
- Histochemical analysis revealed complete loss of striatal fluorescence in both animals, with axonal swelling observed only in the severely impaired monkey.
Conclusions:
- MPTP-induced neurodegeneration, particularly axonal changes in specific brain regions, is strongly correlated with the development of Parkinson-like motor deficits.
- These findings support the hypothesis that neurotoxin-induced alterations in amine levels contribute to the etiology of Parkinsonism.
- Dose and administration regimen are critical factors in MPTP neurotoxicity and the manifestation of motor impairments.