Combination of CDNF and Deep Brain Stimulation Decreases Neurological Deficits in Late-stage Model Parkinson's Disease

Neuroscience. 2018 Mar 15;374:250-263. doi: 10.1016/j.neuroscience.2018.01.052. Epub 2018 Feb 3.

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.

Keywords: 6-hydroxydopamine; CDNF; GDNF; MANF; STN DBS; median forebrain bundle; neurotrophic factor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiparkinson Agents / pharmacology*
  • Apomorphine / pharmacology
  • Combined Modality Therapy
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism
  • Corpus Striatum / pathology
  • Deep Brain Stimulation*
  • Disease Progression
  • Dopamine Agonists / pharmacology
  • Humans
  • Male
  • Motor Activity / drug effects
  • Motor Activity / physiology
  • Nerve Growth Factors / pharmacology*
  • Oxidopamine
  • Parkinsonian Disorders / pathology
  • Parkinsonian Disorders / physiopathology
  • Parkinsonian Disorders / therapy*
  • Rats, Wistar
  • Recombinant Proteins / pharmacology
  • Tyrosine 3-Monooxygenase / metabolism

Substances

  • Antiparkinson Agents
  • CDNF protein, human
  • Dopamine Agonists
  • Nerve Growth Factors
  • Recombinant Proteins
  • Oxidopamine
  • Tyrosine 3-Monooxygenase
  • Apomorphine