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Delayed infusion of GDNF promotes recovery of motor function in the partial lesion model of Parkinson's disease

Kirik, Deniz LU ; Georgievska, Biljana LU ; Rosenblad, Carl and Björklund, Anders LU (2001) In European Journal of Neuroscience 13(8). p.1589-1599
Abstract
Here we studied the effects of glial cell line-derived neurotrophic factor (GDNF) in a rat model that represents the symptomatic stages of Parkinson's disease. GDNF was infused starting 2 weeks after an intrastriatal 6-hydroxydopamine (6-OHDA) lesion in order to halt the ongoing degeneration of the nigrostriatal dopaminergic neurons. GDNF or vehicle was infused in the striatum or the lateral ventricle via an osmotic minipump over a total 4-week period (2-6 weeks postlesion). Motor function was evaluated by the stepping, paw reaching and drug-induced motor asymmetry tests before the pump infusion was initiated, and was repeated once during (5 weeks postlesion) and twice after the withdrawal of the minipumps (7 and 11 weeks postlesion). We... (More)
Here we studied the effects of glial cell line-derived neurotrophic factor (GDNF) in a rat model that represents the symptomatic stages of Parkinson's disease. GDNF was infused starting 2 weeks after an intrastriatal 6-hydroxydopamine (6-OHDA) lesion in order to halt the ongoing degeneration of the nigrostriatal dopaminergic neurons. GDNF or vehicle was infused in the striatum or the lateral ventricle via an osmotic minipump over a total 4-week period (2-6 weeks postlesion). Motor function was evaluated by the stepping, paw reaching and drug-induced motor asymmetry tests before the pump infusion was initiated, and was repeated once during (5 weeks postlesion) and twice after the withdrawal of the minipumps (7 and 11 weeks postlesion). We found that within two weeks following the lesion approximately 40% of the nigral TH-positive neurons were lost. In the vehicle infusion groups there was an additional 20% cell loss between 2 and 12 weeks after the lesion. This latter cell loss occurred mainly in the caudal part of the SN whereas the cell loss in the rostral SN was almost complete within the first two weeks. Ventricular GDNF infusion completely blocked the late degenerating neurons in the caudal SN and had long lasting behavioural effects on the stepping test and amphetamine rotation, extending to 6 weeks after withdrawal of the factor. Striatal infusion affected the motor behaviour transiently during the infusion period but the motor performance of these animals returned to baseline upon cessation of the GDNF delivery, and the delayed nigral cell loss was marginally affected. We conclude that intraventricular GDNF can successfully block the already initiated degenerative process in the substantia nigra, and that the effects achieved via the striatal route, when GDNF is given acutely after the lesion, diminish as the fibre terminal degeneration proceeds. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
6-hydroxydopamine, cell death, glial cell line-derived neurotrophic factor, Parkinson's disease, paw use, sensorimotor behaviour, stepping, stereology, tyrosine hydroxylase
in
European Journal of Neuroscience
volume
13
issue
8
pages
1589 - 1599
publisher
Wiley-Blackwell
external identifiers
  • pmid:11328352
  • scopus:0035011904
ISSN
1460-9568
DOI
language
English
LU publication?
yes
id
47a1a046-3b56-4513-ade1-7cc6c47f7ad1 (old id 1122818)
date added to LUP
2008-07-01 13:56:25
date last changed
2018-06-10 03:53:50
@article{47a1a046-3b56-4513-ade1-7cc6c47f7ad1,
  abstract     = {Here we studied the effects of glial cell line-derived neurotrophic factor (GDNF) in a rat model that represents the symptomatic stages of Parkinson's disease. GDNF was infused starting 2 weeks after an intrastriatal 6-hydroxydopamine (6-OHDA) lesion in order to halt the ongoing degeneration of the nigrostriatal dopaminergic neurons. GDNF or vehicle was infused in the striatum or the lateral ventricle via an osmotic minipump over a total 4-week period (2-6 weeks postlesion). Motor function was evaluated by the stepping, paw reaching and drug-induced motor asymmetry tests before the pump infusion was initiated, and was repeated once during (5 weeks postlesion) and twice after the withdrawal of the minipumps (7 and 11 weeks postlesion). We found that within two weeks following the lesion approximately 40% of the nigral TH-positive neurons were lost. In the vehicle infusion groups there was an additional 20% cell loss between 2 and 12 weeks after the lesion. This latter cell loss occurred mainly in the caudal part of the SN whereas the cell loss in the rostral SN was almost complete within the first two weeks. Ventricular GDNF infusion completely blocked the late degenerating neurons in the caudal SN and had long lasting behavioural effects on the stepping test and amphetamine rotation, extending to 6 weeks after withdrawal of the factor. Striatal infusion affected the motor behaviour transiently during the infusion period but the motor performance of these animals returned to baseline upon cessation of the GDNF delivery, and the delayed nigral cell loss was marginally affected. We conclude that intraventricular GDNF can successfully block the already initiated degenerative process in the substantia nigra, and that the effects achieved via the striatal route, when GDNF is given acutely after the lesion, diminish as the fibre terminal degeneration proceeds.},
  author       = {Kirik, Deniz and Georgievska, Biljana and Rosenblad, Carl and Björklund, Anders},
  issn         = {1460-9568},
  keyword      = {6-hydroxydopamine,cell death,glial cell line-derived neurotrophic factor,Parkinson's disease,paw use,sensorimotor behaviour,stepping,stereology,tyrosine hydroxylase},
  language     = {eng},
  number       = {8},
  pages        = {1589--1599},
  publisher    = {Wiley-Blackwell},
  series       = {European Journal of Neuroscience},
  title        = {Delayed infusion of GDNF promotes recovery of motor function in the partial lesion model of Parkinson's disease},
  url          = {http://dx.doi.org/},
  volume       = {13},
  year         = {2001},
}