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Longitudinal monoaminergic PET imaging of chronic proteasome inhibition in minipigs

Lillethorup, Thea P. ; Glud, Andreas N. ; Alstrup, Aage K.O. ; Noer, Ove ; Nielsen, Erik H.T. ; Schacht, Anna C. ; Landeck, Natalie LU ; Kirik, Deniz LU ; Orlowski, Dariusz and Sørensen, Jens Christian H. , et al. (2018) In Scientific Reports 8(1).
Abstract

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... (More)

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.

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Contribution to journal
publication status
published
subject
in
Scientific Reports
volume
8
issue
1
article number
15715
publisher
Nature Publishing Group
external identifiers
  • pmid:30356172
  • scopus:85055462562
ISSN
2045-2322
DOI
10.1038/s41598-018-34084-5
language
English
LU publication?
yes
id
2b4e6570-34f5-439b-858a-f18641d39a67
date added to LUP
2018-11-14 12:27:25
date last changed
2021-09-29 05:26:02
@article{2b4e6570-34f5-439b-858a-f18641d39a67,
  abstract     = {<p>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 [<sup>11</sup>C]-DTBZ (vesicular monoamine transporter type 2) and [<sup>11</sup>C]-yohimbine (α2-adrenoceptor). [<sup>11</sup>C]-DASB (serotonin transporter) and [<sup>11</sup>C]-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 [<sup>11</sup>C]-DTBZ binding potentials decreased significantly by 16% after 200 μg compared to baseline, but the decrease was not sustained after 400 μg (n = 6). [<sup>11</sup>C]-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 [<sup>11</sup>C]-DASB (n = 5) and increased [<sup>11</sup>C]-PK11195 (n = 3) uptake after 200 μg. These changes may mimic monoaminergic changes and compensatory responses in early Parkinson’s disease.</p>},
  author       = {Lillethorup, Thea P. and Glud, Andreas N. and Alstrup, Aage K.O. and Noer, Ove and Nielsen, Erik H.T. and Schacht, Anna C. and Landeck, Natalie and Kirik, Deniz and Orlowski, Dariusz and Sørensen, Jens Christian H. and Doudet, Doris J. and Landau, Anne M.},
  issn         = {2045-2322},
  language     = {eng},
  number       = {1},
  publisher    = {Nature Publishing Group},
  series       = {Scientific Reports},
  title        = {Longitudinal monoaminergic PET imaging of chronic proteasome inhibition in minipigs},
  url          = {http://dx.doi.org/10.1038/s41598-018-34084-5},
  doi          = {10.1038/s41598-018-34084-5},
  volume       = {8},
  year         = {2018},
}