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Direct intranigral administration of an ubiquitin proteasome system inhibitor in rat: Behavior, positron emission tomography, immunohistochemistry

Mackey, Scott; Jing, Yu; Flores, Joseph LU ; Dinelle, Katie and Doudet, Doris J. (2013) In Experimental Neurology 247. p.19-24
Abstract
Several independent lines of research suggest that disruption of the ubiquitin proteasome system (UPS) may play a role in the pathophysiology of Parkinson's disease. Direct intracerebral injection of UPS inhibitors (e.g. lactacystin) in animals has consistently produced important features of the disease. In this study, a range of lactacystin doses (0.5, 1, 2, 10 and 20 mu g) were injected into the right substantia nigra in rats to determine the ideal dose required to produce a robust and specific lesion of the dopamine nigro-striatal system and motor deficits. Motor behavior, assessed with the tapered ledged beam task, was severely affected in animals that received high doses (10 and 20 mu g) but only mild, impairments were observed in... (More)
Several independent lines of research suggest that disruption of the ubiquitin proteasome system (UPS) may play a role in the pathophysiology of Parkinson's disease. Direct intracerebral injection of UPS inhibitors (e.g. lactacystin) in animals has consistently produced important features of the disease. In this study, a range of lactacystin doses (0.5, 1, 2, 10 and 20 mu g) were injected into the right substantia nigra in rats to determine the ideal dose required to produce a robust and specific lesion of the dopamine nigro-striatal system and motor deficits. Motor behavior, assessed with the tapered ledged beam task, was severely affected in animals that received high doses (10 and 20 mu g) but only mild, impairments were observed in animals that received low doses (0.5, I, and 2 mu g). Positron emission tomography was performed with a dedicated small animal scanner on the rats following the injection of the radio-labeled tracer (+/-)[C-11]dihydrotetrabenazine (DTBZ) which labels vesicular monoamine transporter type 2. Severe loss of [C-11]DTBZ binding in the ipsilateral striatum was observed in the higher dose groups and mild loss was observed in the low dose groups. Stereological cell counting of tyrosine hydroxylase immunoreactive cells in the substantia nigra and the ventral tegmental area indicated a dose dependent loss of dopaminergic neurons. Significant correlations were found between the behavioral motor deficits, striatal [C-11]DTBZ binding and cell counts of tyrosine hydroxylase immunoreactive cells. Taken together these results indicate that intranigral injection of lactacystin produces dose dependent effects on the dopamine nigro-striatal system and a dose of 10 mu g will produce a consistent severe lesion. Published by Elsevier Inc. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Ubiquitin proteasome system, Lactacystin, Rat, Cell counting, Positron, emission tomography, Parkinson's disease
in
Experimental Neurology
volume
247
pages
19 - 24
publisher
Academic Press
external identifiers
  • wos:000323399600004
  • scopus:84876730225
ISSN
0014-4886
DOI
10.1016/j.expneurol.2013.03.021
language
English
LU publication?
yes
id
f74adc03-327d-4a7e-9e5e-481d6c0d43e1 (old id 4025665)
date added to LUP
2013-10-01 15:11:01
date last changed
2019-04-23 01:18:07
@article{f74adc03-327d-4a7e-9e5e-481d6c0d43e1,
  abstract     = {Several independent lines of research suggest that disruption of the ubiquitin proteasome system (UPS) may play a role in the pathophysiology of Parkinson's disease. Direct intracerebral injection of UPS inhibitors (e.g. lactacystin) in animals has consistently produced important features of the disease. In this study, a range of lactacystin doses (0.5, 1, 2, 10 and 20 mu g) were injected into the right substantia nigra in rats to determine the ideal dose required to produce a robust and specific lesion of the dopamine nigro-striatal system and motor deficits. Motor behavior, assessed with the tapered ledged beam task, was severely affected in animals that received high doses (10 and 20 mu g) but only mild, impairments were observed in animals that received low doses (0.5, I, and 2 mu g). Positron emission tomography was performed with a dedicated small animal scanner on the rats following the injection of the radio-labeled tracer (+/-)[C-11]dihydrotetrabenazine (DTBZ) which labels vesicular monoamine transporter type 2. Severe loss of [C-11]DTBZ binding in the ipsilateral striatum was observed in the higher dose groups and mild loss was observed in the low dose groups. Stereological cell counting of tyrosine hydroxylase immunoreactive cells in the substantia nigra and the ventral tegmental area indicated a dose dependent loss of dopaminergic neurons. Significant correlations were found between the behavioral motor deficits, striatal [C-11]DTBZ binding and cell counts of tyrosine hydroxylase immunoreactive cells. Taken together these results indicate that intranigral injection of lactacystin produces dose dependent effects on the dopamine nigro-striatal system and a dose of 10 mu g will produce a consistent severe lesion. Published by Elsevier Inc.},
  author       = {Mackey, Scott and Jing, Yu and Flores, Joseph and Dinelle, Katie and Doudet, Doris J.},
  issn         = {0014-4886},
  keyword      = {Ubiquitin proteasome system,Lactacystin,Rat,Cell counting,Positron,emission tomography,Parkinson's disease},
  language     = {eng},
  pages        = {19--24},
  publisher    = {Academic Press},
  series       = {Experimental Neurology},
  title        = {Direct intranigral administration of an ubiquitin proteasome system inhibitor in rat: Behavior, positron emission tomography, immunohistochemistry},
  url          = {http://dx.doi.org/10.1016/j.expneurol.2013.03.021},
  volume       = {247},
  year         = {2013},
}