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 for this work

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Abstract

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.

Original language	English
Journal	NeuroToxicology
Volume	91
Pages (from-to)	166-176
Number of pages	11
ISSN	0161-813X
DOIs	https://doi.org/10.1016/j.neuro.2022.05.006
Publication status	Published - Jul 2022

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

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Spontaneous partial recovery of striatal dopaminergic uptake despite nigral cell loss in asymptomatic MPTP-lesioned female minipigsFinal published version, 3.71 MBLicence: 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

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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, vol. 91, pp. 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.
In: NeuroToxicology, Vol. 91, 07.2022, p. 166-176.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › 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

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Keywords

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