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Evolution of nerve fiber degeneration in the striatum in the MPTP-treated squirrel monkey
L S Forno1, L E DeLanney, I Irwin
1Department of Pathology, VA Medical Center, Palo Alto, CA.
Abstract:
We have examined the ultrastructure of the striatum in squirrel monkeys 1-5 d after a single sc injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) 2.5 mg/kg. One untreated monkey served as control. We expected to find a dense degeneration of the dopamine terminals, but found instead that the main abnormality consisted of a focal vacuolation of the tissue, perhaps related to the striosome/matrix mosaic of the neostriatum. The vacuolation involved not only terminals, but also other parts of the neuropil. The severity of the destructive process increased from d 1-5. We conclude that MPP+, the toxic metabolite of MPTP, may gain access to the neuropil, either before or after its active uptake into and subsequent destruction of the dopamine terminals. In the present study, abnormalities were observed simultaneously in the striatum and substantia nigra as early as 24 h after MPTP administration. It is, however, possible that the time-course might differ between the two locations with even shorter time intervals or changes in dosage of MPTP.
Insights
Researchers studied the effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on squirrel monkey brains. Unexpectedly, MPTP caused focal brain tissue vacuolation rather than just dopamine terminal degeneration.
Area of Science:
- Neuroscience
- Toxicology
- Primate Research
Background:
- 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin known to cause Parkinsonism.
- The precise mechanism and early ultrastructural changes induced by MPTP in the striatum are not fully understood.
Purpose of the Study:
- To investigate the early ultrastructural changes in the striatum of squirrel monkeys following MPTP administration.
- To characterize the nature of neurotoxicity induced by MPTP and its metabolite MPP+.
Main Methods:
- Squirrel monkeys received a single subcutaneous injection of MPTP (2.5 mg/kg).
- Ultrastructural examination of striatal tissue was performed at 1, 2, 3, 4, and 5 days post-injection.
- One monkey served as an untreated control.
Main Results:
- Instead of expected dopamine terminal degeneration, focal vacuolation of striatal tissue was the primary abnormality observed.
- This vacuolation affected terminals and other neuropil components, with increasing severity from day 1 to day 5.
- Abnormalities were concurrently noted in the striatum and substantia nigra within 24 hours of MPTP administration.
Conclusions:
- The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces focal vacuolation in the striatum, not solely dopamine terminal degeneration.
- The toxic metabolite MPP+ may access the neuropil before or after uptake into dopamine terminals.
- Early, simultaneous changes in the striatum and substantia nigra suggest a rapid neurotoxic cascade.