Combination of CDNF and Deep Brain Stimulation Decreases Neurological Deficits in Late-stage Model Parkinson's Disease. (15th March 2018)

• Record Type: Journal Article
• Authors: Huotarinen, Antti; Penttinen, Anna-Maija; Bäck, Susanne; Voutilainen, Merja H.; Julku, Ulrika; Piepponen, T. Petteri; Männistö, Pekka T.; Saarma, Mart; Tuominen, Raimo; Laakso, Aki; Airavaara, Mikko
• Is Part Of: Neuroscience. Volume 374(2018)
• Page Start: 250
• Page End: 263
• Publication Date: 2018-03-15
• Subjects: 5-HT serotonin, 6-OHDA, 6-hydroxydopamine -- CDNF cerebral dopamine neurotrophic factor -- DA dopamine -- DBS deep brain stimulation -- DOPAC 3, 4-dihydroxyphenylacetic acid -- GDNF glial cell line-derived neurotrophic factor -- HVA homovanillic acid -- IBOT ibotenic acid -- MANF mesencephalic astrocyte-derived neurotrophic factor -- MFB medial forebrain bundle -- NTF neurotrophic factor -- PD Parkinson's disease -- SNpc substantia nigra pars compacta -- STN subthalamic nucleus -- STNL lesion of subthalamic nucleus -- TH tyrosine hydroxylase; CDNF -- MANF -- GDNF -- neurotrophic factor -- median forebrain bundle -- 6-hydroxydopamine -- STN DBS; Neurochemistry -- Periodicals; Neurophysiology -- Periodicals; Neurology -- Periodicals; Neurochimie -- Périodiques; Neurophysiologie -- Périodiques; Neurochemistry; Neurophysiology; Electronic journals; Periodicals; Electronic journals; 612.8
• DOI: 10.1016/j.neuroscience.2018.01.052
• Languages: English
• ISSNs: 0306-4522

Abstract

Highlights: CDNF alone had minimal neurorestorative effect in a MFB 6-OHDA lesion model of PD. CDNF or STN DBS alone or in combination had minimal effect on dopamine biochemistry. CDNF combined to subthalamic nucleus lesion alleviated behavioral defects. Researchon NTF and DBS may lead to combined neuroprotection and symptom control. Abstract: Several neurotrophic factors (NTF) are shown to be neuroprotective and neurorestorative in pre-clinical animal models for Parkinson's disease (PD), particularly in models where striatal dopamine neuron innervation partially exists. The results of clinical trials on late-stage patients have been modest. Subthalamic deep brain stimulation (STN DBS) is a proven treatment for a selected group of advanced PD patients. The cerebral dopamine neurotrophic factor (CDNF) is a promising therapeutic protein, but its effects in animal models of late-stage PD have remained under-researched. The interactions of NTF and STN DBS treatments have not been studied before. We found that a nigral CDNF protein alone had only a marginal effect on the behavioral deficits in a late-stage hemiparkinsonian rat model (6-OHDA MFB). However, CDNF improved the effect of acute STN DBS on front limb use asymmetry at 2 and 3 weeks after CDNF injection. STN lesion—modeling chronic stimulation—had an additive effect in reducing front limb use in the cylinder test and apomorphine-induced rotation. The combination of CDNF and acute STN DBS had a favorable effect on striatal tyrosine hydroxylase. This study presents a novel additive beneficial effect of NTF and STN DBS, which might be explained by the interaction of DBS-induced endogenous NTFs and exogenously injected CDNF. SNpc can be reached via similar trajectories used in clinical STN DBS, and this interaction is an important area for future studies.