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MPTP-induced Parkinsonism in minipigs: A behavioral, biochemical, and histological study
M Mikkelsen1, A Møller, L H Jensen
1Neurological Research Laboratory, Bartholin Institute, Kommunehospitalet, Copenhagen K, Denmark.
Abstract:
Fourteen male Göttingen minipigs were used in this study. Nine were administered N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at a dosage of 1 mg/kg/day, SC, for 6 days, the last five pigs received saline injections for 6 days. All MPTP-treated animals developed Parkinson symptoms, i.e., muscle rigidity, hypokinesia, and impaired coordination within 5 days. The brain levels of dopamine (DA), and its major metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), were determined in caudatum and putamen 2, 14, and 93 days (n = 3/time point) after the last drug administration. In eight of the MPTP-treated animals, striatal DA, DOPAC, and HVA concentrations were reduced from 50 to 95% compared to control animals at all time intervals. Animals with the lowest striatal DA concentrations showed the most severe signs of Parkinsonism. The number of cells in substantia nigra (SN) showed a decline only 3 months after MPTP treatment. The minipigs represent a nonprimate model of MPTP-induced parkinsonism syndromes lasting at least months.
Insights
Göttingen minipigs treated with MPTP developed Parkinsonism symptoms and reduced dopamine levels. This study establishes minipigs as a valuable nonprimate model for MPTP-induced parkinsonism lasting months.
Area of Science:
- Neuroscience
- Pharmacology
- Animal Models
Background:
- Parkinsonism is a neurodegenerative disorder characterized by motor deficits.
- MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is a neurotoxin used to induce Parkinsonism in animal models.
- Nonprimate models are crucial for studying Parkinsonism due to ethical and practical considerations.
Purpose of the Study:
- To evaluate Göttingen minipigs as a nonprimate model for MPTP-induced Parkinsonism.
- To assess the long-term effects of MPTP on dopamine levels and neuronal integrity in the minipig brain.
- To correlate behavioral symptoms with neurochemical and histological changes.
Main Methods:
- Nine male Göttingen minipigs received daily subcutaneous injections of MPTP (1 mg/kg) for six days.
- Control animals received saline injections.
- Brain tissue (caudate and putamen) was analyzed for dopamine (DA) and its metabolites (DOPAC, HVA) at 2, 14, and 93 days post-treatment.
- Substantia nigra (SN) cell counts were assessed at 3 months.
Main Results:
- MPTP-treated minipigs exhibited Parkinsonian symptoms including rigidity, hypokinesia, and impaired coordination.
- Striatal DA, DOPAC, and HVA concentrations were reduced by 50-95% in MPTP-treated animals compared to controls across all time points.
- A decline in substantia nigra cell number was observed three months after MPTP administration.
- A correlation was found between lower striatal DA levels and more severe Parkinsonism symptoms.
Conclusions:
- Göttingen minipigs treated with MPTP develop persistent Parkinsonian symptoms and neurochemical deficits.
- This model demonstrates long-lasting effects, with significant dopamine depletion and neuronal loss in the substantia nigra.
- Minipigs represent a viable nonprimate model for studying MPTP-induced parkinsonism and potential therapeutic interventions.