Deep brain stimulation of the subthalamic nucleus : effect on Parkinsonian motor symptoms and experimental effects with CDNF

Parkinson’s disease (PD) is the second most common neurodegenerative disorder, affecting about 1% of people over 65. The cardinal motor symptoms of PD are mostly due to reduced dopaminergic signaling in the nigrostriatal system and can be effectively treated with dopaminergic medication. However, the most effective treatment, levodopa (L-DOPA), leads to dyskinesias or motor fluctuations. In selected patients, this can be treated with deep brain stimulation of the subthalamic nucleus (STN DBS). Despite extensive studies, the exact mechanisms and optimal targeting of electrodes of STN DBS remain incompletely understood. The current treatments offer only symptomatic relief and no effective neuroprotective therapies are currently available, although neurotrophic factors (NTF) such as CDNF have been promising, especially in animal models. Our aims were to provide a better description of the antiparkinsonian effects of STN DBS both in an experimental rat model and in clinical STN DBS; and to study possible therapeutically favorable interactions of experimental STN DBS and CDNF. Our approach was to use a retrospective clinical study to examine STN DBS electrode locations and reductions in dopaminergic medication and PD symptoms. A significant reduction was observed in both medication and PD symptoms, and more ventrally located electrodes seemed to be more effective, contradicting some earlier studies. We studied the effects of STN DBS in a medial forebrain bundle 6-hydroxydopamine (MFB 6-OHDA) rat model that shows a severe dopaminergic depletion similar to that seen in advanced PD. Stimulation-induced dyskinesias were increased with higher stimulation amplitudes, and these dyskinesias also correlated with an improvement in front-limb use defect. These findings add to our understanding of this relationship and the dose-response of the antiakinetic effect of STN DBS. The combination of STN DBS and CDNF was similarly studied in the MFB 6-OHDA rat model. In particular, the STN lesion, used as a model of chronic STN DBS, had an additive effect with CDNF in reducing the behavioral effects of 6-OHDA hemiparkinsonism, seen both in apomorphine-induced rotations and in the cylinder test for front limb use. These findings indicate that a combination of CDNF and experimental STN DBS has an additive effect in ameliorating the motor deficits of PD. STN DBS and NTF treatments earlier in the course of PD have been suggested as a way to improve their effectiveness. The data presented here provide the first experimental evidence that the effectiveness of STN DBS and NTFs might be improved by administering them simultaneously.