Spontaneous partial recovery of striatal dopaminergic uptake despite nigral cell loss in asymptomatic MPTP-lesioned female minipigs
| Autor: | Thea P. Lillethorup, Ove Noer, Aage Kristian Olsen Alstrup, Caroline C. Real, Kathrine Stokholm, Majken Borup Thomsen, Hamed Zaer, Dariusz Orlowski, Trine Werenberg Mikkelsen, Andreas N. Glud, Erik Holm Toustrup Nielsen, Anna C. Schacht, Michael Winterdahl, David J. Brooks, Jens Christian H. Sørensen, Anne M. Landau |
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| Rok vydání: | 2022 |
| Předmět: |
Parkinson?s disease
EXPRESSION Positron emission tomography Swine Dopamine Toxicology PARKINSONS-DISEASE BINDING TYROSINE-HYDROXYLASE Animals MPTP SUBSTANTIA-NIGRA General Neuroscience Vesicular monoamine transporter 2 Parkinson Disease Corpus Striatum nervous system diseases Minipig Substantia Nigra Disease Models Animal PET PARS COMPACTA nervous system 1-Methyl-4-phenyl-1 2 3 6-tetrahydropyridine GOTTINGEN MINIPIG Swine Miniature Female TREATED MONKEYS PRIMATE MODEL |
| Zdroj: | Lillethorup, T P, Noer, O, Alstrup, A K O, Real, C C, Stokholm, K, Thomsen, M B, Zaer, H, Orlowski, D, Mikkelsen, T W, Glud, A N, Nielsen, E H T, Schacht, A C, Winterdahl, M, Brooks, D J, Sørensen, J C H & Landau, A M 2022, ' Spontaneous Partial Recovery of Striatal Dopaminergic Uptake Despite Nigral Cell Loss in Asymptomatic MPTP-Lesioned Female Minipigs ', NeuroToxicology . https://doi.org/10.1016/j.neuro.2022.05.006 Lillethorup, T P, Noer, O, Alstrup, A K O, Cristiano Real Gregório, C, Stokholm, K, Thomsen, M, Zaer, H, Orlowski, D, Mikkelsen, T W, Glud, AN, Nielsen, E H T, Schacht, A C, Winterdahl, M, Brooks, D J, Sørensen, J C H & Landau, A 2022, ' Spontaneous partial recovery of striatal dopaminergic uptake despite nigral cell loss in asymptomatic MPTP-lesioned female minipigs ', NeuroToxicology, vol. 91, pp. 166-176 . https://doi.org/10.1016/j.neuro.2022.05.006 |
| ISSN: | 1872-9711 |
| Popis: | The Göttingen minipig is a large animal with a gyrencephalic brain that expresses complex behaviour, making it an attractive model for Parkinson's disease research. Here, we investigate the temporal evolution of presynaptic dopaminergic function for 14 months after injections of 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into the minipig using a multi-tracer longitudinal positron emission tomography (PET) design. We injected seven sedated minipigs with 1-2mg/kg of MPTP, and two with saline, three times a week over four weeks. We monitored behavioral deficits using a validated motor scale and walking mat. Brains were imaged with (+)-⍺-[ 11C]-dihydrotetrabenazine ([ 11C]-DTBZ) and [ 18F]-dihydroxyphenylalanine ([ 18F]-FDOPA) PET at baseline and 1, 3, 10 and 14 months after MPTP injection, and immunohistochemistry was used to assess nigral cell loss. The minipigs showed mild bradykinesia and impaired coordination at early timepoints after MPTP. PET revealed decreases of striatal [ 11C]-DTBZ and [ 18F]-FDOPA uptake post-MPTP with partial spontaneous recovery of [ 18F]-FDOPA after 10 months. Postmortem analysis estimated an MPTP-induced nigral loss of 57% tyrosine hydroxylase+ and 43% Nissl-stained cells. Normal motor function despite substantial damage to the dopaminergic system is consistent with prodromal Parkinson's disease, and offers an opportunity for testing disease-modifying therapies. However, partial spontaneous recovery of dopamine terminal function must be taken into account in future studies. |
| Databáze: | OpenAIRE |
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