Subthalamic nucleus lesioning inhibits expression and phosphorylation of c-Jun in nigral neurons in the rat's 6-OHDA model of Parkinson's disease
(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.
(Less)
- author
- Winter, Christine ; Hosmann, Kai ; Harnack, Daniel ; Meissner, Wassilios G. ; Paul, Gesine LU ; Morgenstern, Rudolf and Kupsch, Andreas
- publishing date
- 2006-07
- 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
- external identifiers
-
- pmid:16598703
- scopus:33646693355
- 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
- 2024-01-13 21:17:24
@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}},
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}},
language = {{eng}},
number = {{1}},
pages = {{69--80}},
publisher = {{Wiley}},
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}},
}