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.
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 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.
authors.affiliation: Department of Neurology, Charité-University Medicine Berlin, Campus Charité Mitte, Berlin, Germany. christine.winter@charite.de
authors.forename: Christine
authors.initials: C
authors.lastname: Winter
authors.forename: Kai
authors.initials: K
authors.lastname: Hosmann
authors.forename: Daniel
authors.initials: D
authors.lastname: Harnack
authors.forename: Wassilios
authors.initials: W
authors.lastname: Meissner
authors.forename: Gesine
authors.initials: G
authors.lastname: Paul
authors.forename: Rudolf
authors.initials: R
authors.lastname: Morgenstern
authors.forename: Andreas
authors.initials: A
authors.lastname: Kupsch
mesh_terms: D018663:Adrenergic Agents / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001522:Behavior, Animal / Q000502:physiology; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D016627:Oxidopamine / Q000633:toxicity; D020734:Parkinsonian Disorders / Q000378:metabolism / Q000503:physiopathology*; D010766:Phosphorylation; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013378:Substantia Nigra / Q000378:metabolism* / Q000503:physiopathology; D020531:Subthalamic Nucleus / Q000293:injuries / Q000378:metabolism / Q000503:physiopathology*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D018663:Adrenergic Agents; D016755:Proto-Oncogene Proteins c-jun; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase