Comparative Analysis of the Effects of Neurotrophic Factors CDNF and GDNF in a Nonhuman Primate Model of Parkinson's Disease

Enrique Garea-Rodríguez; Ave Eesmaa; Päivi Lindholm; Christina Schlumbohm; Jessica König; Birgit Meller; Kerstin Krieglstein; Gunther Helms; Mart Saarma; Eberhard Fuchs

doi:10.1371/journal.pone.0149776

Comparative Analysis of the Effects of Neurotrophic Factors CDNF and GDNF in a Nonhuman Primate Model of Parkinson's Disease

PLoS One. 2016 Feb 22;11(2):e0149776. doi: 10.1371/journal.pone.0149776. eCollection 2016.

Authors

Enrique Garea-Rodríguez^{1

2

3}, Ave Eesmaa⁴, Päivi Lindholm⁴, Christina Schlumbohm^{1

5}, Jessica König^{1

5}, Birgit Meller⁶, Kerstin Krieglstein⁷, Gunther Helms⁸, Mart Saarma⁴, Eberhard Fuchs^{1

3}

Affiliations

¹ Clinical Neurobiology Laboratory, German Primate Center, Göttingen, Germany.
² Department of Neuroanatomy Institute of Anatomy and Cell Biology, Albert-Ludwigs-University Freiburg, Freiburg, Germany.
³ Center for Molecular Physiology of the Brain (CMPB), University of Göttingen, Göttingen, Germany.
⁴ Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
⁵ Encepharm, Göttingen, Germany.
⁶ Department of Nuclear Medicine, University Medical Center, Georg-August-University Göttingen, Göttingen, Germany.
⁷ Department of Molecular Embryology, Institute for Anatomy and Cell Biology, Albert-Ludwigs-University Freiburg, Freiburg, Germany.
⁸ Department of Cognitive Neurology, University Medical Center, Georg-August-University Göttingen, Göttingen, Germany.

Abstract

Cerebral dopamine neurotrophic factor (CDNF) belongs to a newly discovered family of evolutionarily conserved neurotrophic factors. We demonstrate for the first time a therapeutic effect of CDNF in a unilateral 6-hydroxydopamine (6-OHDA) lesion model of Parkinson's disease in marmoset monkeys. Furthermore, we tested the impact of high chronic doses of human recombinant CDNF on unlesioned monkeys and analyzed the amino acid sequence of marmoset CDNF. The severity of 6-OHDA lesions and treatment effects were monitored in vivo using 123I-FP-CIT (DaTSCAN) SPECT. Quantitative analysis of 123I-FP-CIT SPECT showed a significant increase of dopamine transporter binding activity in lesioned animals treated with CDNF. Glial cell line-derived neurotrophic factor (GDNF), a well-characterized and potent neurotrophic factor for dopamine neurons, served as a control in a parallel comparison with CDNF. By contrast with CDNF, only single animals responded to the treatment with GDNF, but no statistical difference was observed in the GDNF group. However, increased numbers of tyrosine hydroxylase immunoreactive neurons, observed within the lesioned caudate nucleus of GDNF-treated animals, indicate a strong bioactive potential of GDNF.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Callithrix
Disease Models, Animal
Dopaminergic Neurons / drug effects
Dopaminergic Neurons / metabolism
Glial Cell Line-Derived Neurotrophic Factor / metabolism*
Magnetic Resonance Imaging
Nerve Growth Factors / metabolism*
Oxidopamine / pharmacology
Parkinson Disease / metabolism*
Tomography, Emission-Computed, Single-Photon

Substances

Glial Cell Line-Derived Neurotrophic Factor
Nerve Growth Factors
Oxidopamine

Grants and funding

EGR was funded by EU ERA-Net NEURON (PARKCDNF) (http://www.neuron-eranet.eu/). The study was partially supported by the DFG Research Center Molecular Physiology of the Brain (CMPB) (http://www.cmpb.uni-goettingen.de/) and by a S. Jusélius Foundation (http://www.sigridjuselius.fi/foundation) grant to MS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.