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Subthalamic nucleus lesioning inhibits expression and phosphorylation of c-Jun in nigral neurons in the rat's 6-OHDA model of Parkinson's disease

Winter, Christine ; Hosmann, Kai ; Harnack, Daniel ; Meissner, Wassilios G. ; Paul, Gesine LU ; Morgenstern, Rudolf and Kupsch, Andreas (2006) In Synapse 60(1). p.69-80
Abstract

Parkinson's Disease (PD) is characterized by a loss of nigral dopamine (DA) neurons, followed by a striatal DA deficit. Inhibition of the subthalamic nucleus (STN) reverses L-DOPA sensitive motor symptoms and improves efficacy of pharmacotherapy in PD-patients. The underlying mechanism of these effects, however, remains largely unknown. Previously, we could show in the rat's 6-hydroxyDA (6-OHDA) model of PD that ablative STN-lesioning exerts functionally neuroprotective effects on the DAergic nigrostriatal pathway against 6-OHDA toxicity, in terms of elevating the number of tyrosine hydroxylase (TH)-expressing neurons rather than enhancing the total number of cells surviving 2 and 6 weeks post lesioning, as assessed via fluorogold... (More)

Parkinson's Disease (PD) is characterized by a loss of nigral dopamine (DA) neurons, followed by a striatal DA deficit. Inhibition of the subthalamic nucleus (STN) reverses L-DOPA sensitive motor symptoms and improves efficacy of pharmacotherapy in PD-patients. The underlying mechanism of these effects, however, remains largely unknown. Previously, we could show in the rat's 6-hydroxyDA (6-OHDA) model of PD that ablative STN-lesioning exerts functionally neuroprotective effects on the DAergic nigrostriatal pathway against 6-OHDA toxicity, in terms of elevating the number of tyrosine hydroxylase (TH)-expressing neurons rather than enhancing the total number of cells surviving 2 and 6 weeks post lesioning, as assessed via fluorogold staining. These data were correlated with increased functional recovery of 6-OHDA-lesioned rats with preceding STN-lesioning. Here, we extend the previous study design to observation periods of up to 12 weeks to assess long-term effects. Furthermore, to elucidate cellular mechanisms underlying potential neuroprotective effects, we explore the regulation of cellular markers involved in neurodegenerative cascades via immunocytochemistry. We show that preceding STN-lesioning significantly inhibits 6-OHDA induced expression/phosphorylation of the transcription factor c-Jun in surviving nigral neurons in comparison with controls. However, we also demonstrate that functionally neuroprotective effects of preceding STN-lesioning subside after 12 weeks, as assessed with TH immunostaining. We therefore conclude that c-Jun induction/phosphorylation is involved in 6-OHDA toxicity and that STN-lesioning transiently preserves of dopaminergic phenotype of nigral neurons partially via delaying the induction and attenuating the expression and phosphorylation of c-Jun.

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publishing date
type
Contribution to journal
publication status
published
keywords
Adrenergic Agents, Animals, Apoptosis, Behavior, Animal, Disease Models, Animal, Immunohistochemistry, In Situ Nick-End Labeling, Male, Neurons, Oxidopamine, Parkinsonian Disorders, Phosphorylation, Proto-Oncogene Proteins c-jun, Rats, Rats, Wistar, Substantia Nigra, Subthalamic Nucleus, Tyrosine 3-Monooxygenase, Journal Article, Research Support, Non-U.S. Gov't
in
Synapse
volume
60
issue
1
pages
12 pages
publisher
Wiley Periodicals, Inc
external identifiers
  • scopus:33646693355
  • pmid:16598703
ISSN
0887-4476
DOI
10.1002/syn.20269
language
English
LU publication?
no
id
10d748f3-5101-492a-ae34-8ebb4eaa9cff
date added to LUP
2017-05-18 11:07:35
date last changed
2021-03-24 02:59:15
@article{10d748f3-5101-492a-ae34-8ebb4eaa9cff,
  abstract     = {<p>Parkinson's Disease (PD) is characterized by a loss of nigral dopamine (DA) neurons, followed by a striatal DA deficit. Inhibition of the subthalamic nucleus (STN) reverses L-DOPA sensitive motor symptoms and improves efficacy of pharmacotherapy in PD-patients. The underlying mechanism of these effects, however, remains largely unknown. Previously, we could show in the rat's 6-hydroxyDA (6-OHDA) model of PD that ablative STN-lesioning exerts functionally neuroprotective effects on the DAergic nigrostriatal pathway against 6-OHDA toxicity, in terms of elevating the number of tyrosine hydroxylase (TH)-expressing neurons rather than enhancing the total number of cells surviving 2 and 6 weeks post lesioning, as assessed via fluorogold staining. These data were correlated with increased functional recovery of 6-OHDA-lesioned rats with preceding STN-lesioning. Here, we extend the previous study design to observation periods of up to 12 weeks to assess long-term effects. Furthermore, to elucidate cellular mechanisms underlying potential neuroprotective effects, we explore the regulation of cellular markers involved in neurodegenerative cascades via immunocytochemistry. We show that preceding STN-lesioning significantly inhibits 6-OHDA induced expression/phosphorylation of the transcription factor c-Jun in surviving nigral neurons in comparison with controls. However, we also demonstrate that functionally neuroprotective effects of preceding STN-lesioning subside after 12 weeks, as assessed with TH immunostaining. We therefore conclude that c-Jun induction/phosphorylation is involved in 6-OHDA toxicity and that STN-lesioning transiently preserves of dopaminergic phenotype of nigral neurons partially via delaying the induction and attenuating the expression and phosphorylation of c-Jun.</p>},
  author       = {Winter, Christine and Hosmann, Kai and Harnack, Daniel and Meissner, Wassilios G. and Paul, Gesine and Morgenstern, Rudolf and Kupsch, Andreas},
  issn         = {0887-4476},
  language     = {eng},
  number       = {1},
  pages        = {69--80},
  publisher    = {Wiley Periodicals, Inc},
  series       = {Synapse},
  title        = {Subthalamic nucleus lesioning inhibits expression and phosphorylation of c-Jun in nigral neurons in the rat's 6-OHDA model of Parkinson's disease},
  url          = {http://dx.doi.org/10.1002/syn.20269},
  doi          = {10.1002/syn.20269},
  volume       = {60},
  year         = {2006},
}