Longitudinal monoaminergic PET imaging of chronic proteasome inhibition in minipigs

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Longitudinal monoaminergic PET imaging of chronic proteasome inhibition in minipigs. / Lillethorup, Thea Pinholt; GLUD, AN; Alstrup, Aage Kristian Olsen; Noer, Ove; Nielsen, Erik Holm Toustrup; Schacht, Anna Christina; Landeck, Natalie; Kirik, Deniz; Orlowski, Dariusz; Sørensen, Jens Christian Hedemann; Doudet, Doris J; Landau, Anne.

In: Scientific Reports, Vol. 8, 15715, 24.10.2018.

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@article{89a959b8ba094ab38467734271f0bee0,
title = "Longitudinal monoaminergic PET imaging of chronic proteasome inhibition in minipigs",
abstract = "Impairment of the ubiquitin proteasome system has been implicated in Parkinson{\textquoteright}s disease. We used positron emission tomography to investigate longitudinal effects of chronic intracerebroventricular exposure to the proteasome inhibitor lactacystin on monoaminergic projections and neuroinflammation. G{\"o}ttingen minipigs were implanted in the cisterna magna with a catheter connected to a subcutaneous injection port. Minipigs were imaged at baseline and after cumulative doses of 200 and 400 μg lactacystin, respectively. Main radioligands included [11C]-DTBZ (vesicular monoamine transporter type 2) and [11C]-yohimbine (α2-adrenoceptor). [11C]-DASB (serotonin transporter) and [11C]-PK11195 (activated microglia) became available later in the study and we present their results in a smaller subset of animals for information purposes only. Striatal [11C]-DTBZ binding potentials decreased significantly by 16% after 200 μg compared to baseline, but the decrease was not sustained after 400 μg (n = 6). [11C]-yohimbine volume of distribution increased by 18–25% in the pons, grey matter and the thalamus after 200 μg, which persisted at 400 μg (n = 6). In the later subset of minipigs, we observed decreased [11C]-DASB (n = 5) and increased [11C]-PK11195 (n = 3) uptake after 200 μg. These changes may mimic monoaminergic changes and compensatory responses in early Parkinson{\textquoteright}s disease.",
author = "Lillethorup, {Thea Pinholt} and AN GLUD and Alstrup, {Aage Kristian Olsen} and Ove Noer and Nielsen, {Erik Holm Toustrup} and Schacht, {Anna Christina} and Natalie Landeck and Deniz Kirik and Dariusz Orlowski and S{\o}rensen, {Jens Christian Hedemann} and Doudet, {Doris J} and Anne Landau",
year = "2018",
month = oct,
day = "24",
doi = "10.1038/s41598-018-34084-5",
language = "English",
volume = "8",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",

}

RIS

TY - JOUR

T1 - Longitudinal monoaminergic PET imaging of chronic proteasome inhibition in minipigs

AU - Lillethorup, Thea Pinholt

AU - GLUD, AN

AU - Alstrup, Aage Kristian Olsen

AU - Noer, Ove

AU - Nielsen, Erik Holm Toustrup

AU - Schacht, Anna Christina

AU - Landeck, Natalie

AU - Kirik, Deniz

AU - Orlowski, Dariusz

AU - Sørensen, Jens Christian Hedemann

AU - Doudet, Doris J

AU - Landau, Anne

PY - 2018/10/24

Y1 - 2018/10/24

N2 - Impairment of the ubiquitin proteasome system has been implicated in Parkinson’s disease. We used positron emission tomography to investigate longitudinal effects of chronic intracerebroventricular exposure to the proteasome inhibitor lactacystin on monoaminergic projections and neuroinflammation. Göttingen minipigs were implanted in the cisterna magna with a catheter connected to a subcutaneous injection port. Minipigs were imaged at baseline and after cumulative doses of 200 and 400 μg lactacystin, respectively. Main radioligands included [11C]-DTBZ (vesicular monoamine transporter type 2) and [11C]-yohimbine (α2-adrenoceptor). [11C]-DASB (serotonin transporter) and [11C]-PK11195 (activated microglia) became available later in the study and we present their results in a smaller subset of animals for information purposes only. Striatal [11C]-DTBZ binding potentials decreased significantly by 16% after 200 μg compared to baseline, but the decrease was not sustained after 400 μg (n = 6). [11C]-yohimbine volume of distribution increased by 18–25% in the pons, grey matter and the thalamus after 200 μg, which persisted at 400 μg (n = 6). In the later subset of minipigs, we observed decreased [11C]-DASB (n = 5) and increased [11C]-PK11195 (n = 3) uptake after 200 μg. These changes may mimic monoaminergic changes and compensatory responses in early Parkinson’s disease.

AB - Impairment of the ubiquitin proteasome system has been implicated in Parkinson’s disease. We used positron emission tomography to investigate longitudinal effects of chronic intracerebroventricular exposure to the proteasome inhibitor lactacystin on monoaminergic projections and neuroinflammation. Göttingen minipigs were implanted in the cisterna magna with a catheter connected to a subcutaneous injection port. Minipigs were imaged at baseline and after cumulative doses of 200 and 400 μg lactacystin, respectively. Main radioligands included [11C]-DTBZ (vesicular monoamine transporter type 2) and [11C]-yohimbine (α2-adrenoceptor). [11C]-DASB (serotonin transporter) and [11C]-PK11195 (activated microglia) became available later in the study and we present their results in a smaller subset of animals for information purposes only. Striatal [11C]-DTBZ binding potentials decreased significantly by 16% after 200 μg compared to baseline, but the decrease was not sustained after 400 μg (n = 6). [11C]-yohimbine volume of distribution increased by 18–25% in the pons, grey matter and the thalamus after 200 μg, which persisted at 400 μg (n = 6). In the later subset of minipigs, we observed decreased [11C]-DASB (n = 5) and increased [11C]-PK11195 (n = 3) uptake after 200 μg. These changes may mimic monoaminergic changes and compensatory responses in early Parkinson’s disease.

UR - https://rdcu.be/9XQ9

U2 - 10.1038/s41598-018-34084-5

DO - 10.1038/s41598-018-34084-5

M3 - Journal article

C2 - 30356172

VL - 8

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

M1 - 15715

ER -