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

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.