Spontaneous partial recovery of striatal dopaminergic uptake despite nigral cell loss in asymptomatic MPTP-lesioned female minipigs

Thea Pinholt Lillethorup; Ove Noer; Aage Kristian Olsen Alstrup; Caroline Cristiano Real Gregório; Kathrine Stokholm; Majken Thomsen; Hamed Zaer; Dariusz Orlowski; Trine Werenberg Mikkelsen; AN Glud; Erik Holm Toustrup Nielsen; Anna Christina Schacht; Michael Winterdahl; David J Brooks; Jens Christian Hedemann Sørensen; Anne Landau

doi:10.1016/j.neuro.2022.05.006

Spontaneous partial recovery of striatal dopaminergic uptake despite nigral cell loss in asymptomatic MPTP-lesioned female minipigs

Thea Pinholt Lillethorup, Ove Noer, Aage Kristian Olsen Alstrup, Caroline Cristiano Real Gregório, Kathrine Stokholm, Majken Thomsen, Hamed Zaer, Dariusz Orlowski, Trine Werenberg Mikkelsen, AN Glud, Erik Holm Toustrup Nielsen, Anna Christina Schacht, Michael Winterdahl, David J Brooks, Jens Christian Hedemann Sørensen, Anne Landau^*

^*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

1 Citationer (Scopus)

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Abstract

The gold standard animal model of Parkinson’s disease is the non-human primate rendered parkinsonian
with the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxin. Low availability, ethical issues, and
primate-specific biohazards make alternative large animal models necessary. Here, we investigate the temporal evolution of presynaptic dopaminergic function after MPTP in another large animal model, the Göttingen minipig. We subcutaneously injected seven sedated minipigs with 1–2 mg/kg of MPTP, and two minipigs with saline, three times a week over 4 weeks. We monitored behavioral deficits using a validated motor scale and a Gait4Dog® walking mat. Minipig brains were imaged with (+)-⍺-[11C]-dihydrotetrabenazine ([11C]-DTBZ) and [18F]-fluorodopa ([18F]-FDOPA) PET at baseline and 1, 3, 9 and 12 months after the final MPTP injection. Immunohistochemical tyrosine hydroxylase (TH) staining was used to assay nigral TH + area loss post-mortem. The minipigs showed only mild bradykinesia and impaired coordination at early timepoints after MPTP. PET revealed decreases of striatal [11C]-DTBZ and [18F]-FDOPA uptake post-MPTP with a partial spontaneous recovery of [18F]-FDOPA after 9 months. Postmortem histological analysis showed a loss of 71% TH-immunopositive area in the substantia nigra. When testing the efficacy of putative neuroprotective agents, partial spontaneous recovery of dopamine terminal function must be taken into account in the MPTP minipig model of parkinsonism.

Originalsprog	Engelsk
Tidsskrift	NeuroToxicology
Vol/bind	91
Sider (fra-til)	166-176
Antal sider	11
ISSN	0161-813X
DOI	https://doi.org/10.1016/j.neuro.2022.05.006
Status	Udgivet - jul. 2022

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10.1016/j.neuro.2022.05.006Licens: CC BY

Spontaneous partial recovery of striatal dopaminergic uptake despite nigral cell loss in asymptomatic MPTP-lesioned female minipigsForlagets udgivne version, 3,71 MBLicens: CC BY

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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, 91, 166-176. https://doi.org/10.1016/j.neuro.2022.05.006

@article{6d064fbaba52406cb8c0b13140b3b752,

title = "Spontaneous partial recovery of striatal dopaminergic uptake despite nigral cell loss in asymptomatic MPTP-lesioned female minipigs",

abstract = "The G{\"o}ttingen minipig is a large animal with a gyrencephalic brain that expresses –complex behavior, 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 1–2 mg/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.",

keywords = "BINDING, Dopamine, EXPRESSION, GOTTINGEN MINIPIG, MPTP, Minipig, PARKINSONS-DISEASE, PARS COMPACTA, PET, PRIMATE MODEL, Parkinson?s disease, Positron emission tomography, SUBSTANTIA-NIGRA, TREATED MONKEYS, TYROSINE-HYDROXYLASE, Vesicular monoamine transporter 2",

author = "Lillethorup, {Thea Pinholt} and Ove Noer and Alstrup, {Aage Kristian Olsen} and {Cristiano Real Greg{\'o}rio}, Caroline and Kathrine Stokholm and Majken Thomsen and Hamed Zaer and Dariusz Orlowski and Mikkelsen, {Trine Werenberg} and AN Glud and Nielsen, {Erik Holm Toustrup} and Schacht, {Anna Christina} and Michael Winterdahl and Brooks, {David J} and S{\o}rensen, {Jens Christian Hedemann} and Anne Landau",

year = "2022",

month = jul,

doi = "10.1016/j.neuro.2022.05.006",

language = "English",

volume = "91",

pages = "166--176",

journal = "NeuroToxicology",

issn = "0161-813X",

publisher = "Elsevier B.V.",

}

Lillethorup, TP , Noer, O , Alstrup, AKO , Cristiano Real Gregório, C, Stokholm, K, Thomsen, M , Zaer, H , Orlowski, D , Mikkelsen, TW , Glud, AN , Nielsen, EHT, Schacht, AC, Winterdahl, M , Brooks, DJ , Sørensen, JCH & Landau, A 2022, 'Spontaneous partial recovery of striatal dopaminergic uptake despite nigral cell loss in asymptomatic MPTP-lesioned female minipigs', NeuroToxicology, bind 91, s. 166-176. https://doi.org/10.1016/j.neuro.2022.05.006

Spontaneous partial recovery of striatal dopaminergic uptake despite nigral cell loss in asymptomatic MPTP-lesioned female minipigs. / Lillethorup, Thea Pinholt ; Noer, Ove ; Alstrup, Aage Kristian Olsen et al.
I: NeuroToxicology, Bind 91, 07.2022, s. 166-176.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

TY - JOUR

T1 - Spontaneous partial recovery of striatal dopaminergic uptake despite nigral cell loss in asymptomatic MPTP-lesioned female minipigs

AU - Lillethorup, Thea Pinholt

AU - Noer, Ove

AU - Alstrup, Aage Kristian Olsen

AU - Cristiano Real Gregório, Caroline

AU - Stokholm, Kathrine

AU - Thomsen, Majken

AU - Zaer, Hamed

AU - Orlowski, Dariusz

AU - Mikkelsen, Trine Werenberg

AU - Glud, AN

AU - Nielsen, Erik Holm Toustrup

AU - Schacht, Anna Christina

AU - Winterdahl, Michael

AU - Brooks, David J

AU - Sørensen, Jens Christian Hedemann

AU - Landau, Anne

PY - 2022/7

Y1 - 2022/7

N2 - The Göttingen minipig is a large animal with a gyrencephalic brain that expresses –complex behavior, 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 1–2 mg/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.

AB - The Göttingen minipig is a large animal with a gyrencephalic brain that expresses –complex behavior, 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 1–2 mg/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.

KW - BINDING

KW - Dopamine

KW - EXPRESSION

KW - GOTTINGEN MINIPIG

KW - MPTP

KW - Minipig

KW - PARKINSONS-DISEASE

KW - PARS COMPACTA

KW - PET

KW - PRIMATE MODEL

KW - Parkinson?s disease

KW - Positron emission tomography

KW - SUBSTANTIA-NIGRA

KW - TREATED MONKEYS

KW - TYROSINE-HYDROXYLASE

KW - Vesicular monoamine transporter 2

UR - http://www.scopus.com/inward/record.url?scp=85133918522&partnerID=8YFLogxK

U2 - 10.1016/j.neuro.2022.05.006

DO - 10.1016/j.neuro.2022.05.006

M3 - Journal article

C2 - 35569565

SN - 0161-813X

VL - 91

SP - 166

EP - 176

JO - NeuroToxicology

JF - NeuroToxicology

ER -

Spontaneous partial recovery of striatal dopaminergic uptake despite nigral cell loss in asymptomatic MPTP-lesioned female minipigs

Abstract

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