Skip to main content

Main menu

  • HOME
  • CONTENT
    • Early Release
    • Featured
    • Current Issue
    • Issue Archive
    • Blog
    • Collections
    • Podcast
  • TOPICS
    • Cognition and Behavior
    • Development
    • Disorders of the Nervous System
    • History, Teaching and Public Awareness
    • Integrative Systems
    • Neuronal Excitability
    • Novel Tools and Methods
    • Sensory and Motor Systems
  • ALERTS
  • FOR AUTHORS
  • ABOUT
    • Overview
    • Editorial Board
    • For the Media
    • Privacy Policy
    • Contact Us
    • Feedback
  • SUBMIT

User menu

Search

  • Advanced search
eNeuro

eNeuro

Advanced Search

 

  • HOME
  • CONTENT
    • Early Release
    • Featured
    • Current Issue
    • Issue Archive
    • Blog
    • Collections
    • Podcast
  • TOPICS
    • Cognition and Behavior
    • Development
    • Disorders of the Nervous System
    • History, Teaching and Public Awareness
    • Integrative Systems
    • Neuronal Excitability
    • Novel Tools and Methods
    • Sensory and Motor Systems
  • ALERTS
  • FOR AUTHORS
  • ABOUT
    • Overview
    • Editorial Board
    • For the Media
    • Privacy Policy
    • Contact Us
    • Feedback
  • SUBMIT
PreviousNext
Research ArticleNew Research, Disorders of the Nervous System

Evidence for an Additive Neurorestorative Effect of Simultaneously Administered CDNF and GDNF in Hemiparkinsonian Rats: Implications for Different Mechanism of Action

Merja H. Voutilainen, Francesca De Lorenzo, Polina Stepanova, Susanne Bäck, Li-Ying Yu, Päivi Lindholm, Eeva Pörsti, Mart Saarma, Pekka T. Männistö and Raimo K. Tuominen
eNeuro 22 February 2017, 4 (1) ENEURO.0117-16.2017; DOI: https://doi.org/10.1523/ENEURO.0117-16.2017
Merja H. Voutilainen
1Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, Viikki Biocenter, University of Helsinki, FIN-00014 Helsinki, Finland
2Institute of Biotechnology, Viikki Biocenter, University of Helsinki, FIN-00014 Helsinki, Finland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Merja H. Voutilainen
Francesca De Lorenzo
2Institute of Biotechnology, Viikki Biocenter, University of Helsinki, FIN-00014 Helsinki, Finland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Polina Stepanova
2Institute of Biotechnology, Viikki Biocenter, University of Helsinki, FIN-00014 Helsinki, Finland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Susanne Bäck
1Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, Viikki Biocenter, University of Helsinki, FIN-00014 Helsinki, Finland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Li-Ying Yu
2Institute of Biotechnology, Viikki Biocenter, University of Helsinki, FIN-00014 Helsinki, Finland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Päivi Lindholm
2Institute of Biotechnology, Viikki Biocenter, University of Helsinki, FIN-00014 Helsinki, Finland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Päivi Lindholm
Eeva Pörsti
1Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, Viikki Biocenter, University of Helsinki, FIN-00014 Helsinki, Finland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mart Saarma
2Institute of Biotechnology, Viikki Biocenter, University of Helsinki, FIN-00014 Helsinki, Finland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Mart Saarma
Pekka T. Männistö
1Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, Viikki Biocenter, University of Helsinki, FIN-00014 Helsinki, Finland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Raimo K. Tuominen
1Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, Viikki Biocenter, University of Helsinki, FIN-00014 Helsinki, Finland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF
Loading

Article Figures & Data

Figures

  • Tables
  • Figure 1.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Figure 1.

    The effect of CDNF and GDNF alone or their coadministration on amphetamine-induced rotation. A, Experimental design. Rats were administered 6-OHDA (20 µg) unilaterally in the striatum. Four weeks later, the rats were given a unilateral intrastriatal injection of CDNF (1 µg), GDNF (1 µg), CDNF (2.5 µg), GDNF (2.5 µg), CDNF (5 µg), or GDNF (5 µg) alone or combination of them. The rotational behavior was measured 3, 6, 8, 10, and 12 weeks after lesion. B, Amphetamine-induced ipsilateral rotations at 12 weeks after lesion in rats treated with vehicle, CDNF (2.5 µg), GDNF (1 µg), or combinations of GDNF (1 µg) with either CDNF (1 µg), CDNF (2.5 µg), or CDNF (5 µg). C, Amphetamine-induced ipsilateral rotations at 12 weeks after lesion in rats treated with vehicle, CDNF (1 µg), alone, or in combination with GDNF (1 µg), GDNF (2.5 µg), or GDNF (5 µg). D, Amphetamine-induced ipsilateral rotations at 12 weeks after lesion in rats treated with vehicle, CDNF (2.5 µg) and GDNF (2.5 µg) alone or in combination; CDNF (5 µg) and GDNF (5 µg) alone or in combination. Means ± SEM are shown; n = 8–10 in each group. p < 0.05 Tukey/Kramer post hoc analysis after one-way ANOVA. *p < 0.05, **p < 0.01.

  • Figure 2.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Figure 2.

    Number of TH-positive and Nissl-positive cells in the SNpc and OD of TH-positive fibers in the STR. A, The effect of CDNF (2.5 μg) alone and GDNF (1 μg) alone, or the combination of CDNF (2.5 μg) + GDNF (1 μg) on TH-positive cell bodies in the SNpc analyzed at 12 weeks after lesion. The effect of the combination of CDNF (2.5 μg) and GDNF (1 μg) differed significantly from the vehicle-treated group (p < 0.05). B, Analyses of Nissl-stained cell bodies in SNpc. Results were in line with TH-positive cell body counts from SNpc. C, The effect of CDNF (2.5 μg) alone, GDNF (1 μg) alone, or the combination of CDNF (2.5 μg) and GDNF (1 μg) on TH-positive fibers in the STR. CDNF and the combination of CDNF and GDNF partly rescue TH-positive fibers in the STR. D, Representative TH-stained striatal sections for each treatment. Mean ± SEM in (A, B) n = 7-12 and in (C) n = 7-12 in each group. Tukey/Kramer post hoc analysis after one-way ANOVA. *p < 0.05, ****p < 0.0001.

  • Figure 3.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Figure 3.

    Different effects of CDNF and GDNF on ERK1/2 and PI3K/AKT pathways in naïve rats. Ability of CDNF and GDNF to activate MAPK or PI3K/AKT/mTOR pathways was studied injecting CDNF (2.5 µg), GDNF (1 µg), or their combination into the left STR (LSTR) of naïve rats (A–D). Sham-operated rats received PBS into LSTR. A, B, In rats dissected 1 h after NTF injection, GDNF activated ERK1/2 and PI3K/AKT pathway whereas CDNF had no effect. D, In rats dissected 4 h after CDNF injection the PI3K/AKT pathway was activated in nonlesioned brains (D), whereas the ERK1/2 pathway was not affected (C). Representative Western blot images of ERK1/2, p-ERK1/2, PI3K/AKT, and p-PI3K/AKT are shown. Mean ± SEM, n = 3-6 in each group. Tukey/Kramer post hoc analysis after one-way ANOVA.

  • Figure 4.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Figure 4.

    Differences in activation of ERK1/2 and PI3K/AKT pathways after intrastriatal injection of CDNF and GDNF or their combination in 6-OHDA-lesioned rats. When the rats were dissected 4 h after the NTF injection, the MAPK or PI3K/AKT pathway was not activated in 6-OHDA-lesioned rats. CDNF (2.5 µg) did not have significant effect on MAPK (A) or PI3K/AKT/mTOR (B) pathways. CDNF (2.5 µg) increased ribosomal protein S6 phosphorylation in the STR in comparison to rats treated with GDNF (1 µg) (C). The number of pErk-positive cells in STR was increased by all treatments (D), while there was no effect on OD of pAkt-positive fibers in STR (E). Tukey/Kramer post hoc analysis after one-way ANOVA. *p < 0.05, **p < 0.01.

  • Figure 5.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Figure 5.

    Effects of CDNF and GDNF and their combination on ER stress-triggered UPR markers in cultured DA neurons and in rat 6-OHDA model in vivo. A–C, E13 dopamine neurons were cultured 5-7 d with GDNF (50 ng/ml). Then, the cultures were treated with thapsigargin (200 nM) to induce ER stress. CDNF (100 ng/ml), GDNF (50 ng/ml), or their combination was added to the cultures at the same time. The expression levels were normalized to the levels of β-actin in the same samples. CDNF and the combination reduced expression of ATF6 mRNA (A). Levels of Xbp1-sp (B) and GPR-78 (C) were not changed. D--F, Effect of CDNF and GDNF on ER stress markers in the rat 6-OHDA model. D, Experimental design for ER stress markers analyses. Rats were administered 6-OHDA (20 µg) unilaterally into the left striatum (L). Four weeks later, the rats received a single injection of either vehicle (PBS), CDNF (2.5 µg), GDNF (1 µg), or their combination into the lesioned striatum. Rats were killed 4 h after NTF injection, and striata were dissected for Western blot analyses. E, Injection of CDNF decreases GRP78 protein levels in striata of 6-OHDA-lesioned rats compared with PBS (p = 0.2) or GDNF treatment (p < 0.05). The level of expression is expressed as % of intact contralateral site of the brain. Representative Western blot images of GRP78 expression. Control shows basal level of GRP78 in a naïve rat brain. β-tubulin is used as loading control. F, CDNF-treated animals showed a decrease in the activation of P-eIF2α compared with the vehicle-treated rats. Representative Western blot images of P-eIF2α and total eIF2α. Control shows basal level of P-eIF2α and total eIF2α in a naïve rat brain. Mean ± SEM. n = 5-6 in each group. Tukey/Kramer post hoc analysis after one-way ANOVA. **p < 0.01.

  • Figure 6.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Figure 6.

    Effect of CDNF, GDNF, and their combination on TH- and DAT protein levels in 6-OHDA-lesioned and sham-lesioned brain. Four weeks after lesioning, sham-lesioned or 6-OHDA-lesioned rats received an intrastriatal injection of vehicle (VEH), CDNF, GDNF, or a combination of CDNF and GDNF. Eight weeks after lesioning, rat SN and striatum (STR) protein expression were analyzed from total protein samples (13 µg for SN samples and 15 µg for STR samples, respectively) using Western blotting. 6-OHDA lesion resulted in a marked decrease in both TH and DAT protein levels in the SN (A, B) and STR (C, D). None of the treatments were able to significantly affect the TH and DAT protein levels after sham or 6-OHDA lesion, although GDNF alone or in combination with CDNF tended to decrease the levels of TH in sham-lesioned STR (C). Results are shown as the group mean ± SEM of protein band density relative to the density of a control sample (pooled from four naive STR or SN) and β-actin. n = 3-5 in each group. Tukey/Kramer post hoc analysis after one-way ANOVA. TH-levels in SN (A) and striatum (C) and DAT-levels in SN (B) and STR (D) did not show statistically significant changes.

Tables

  • Figures
    • View popup
    Table 1:

    Statistical table

    Symbol in textDatasetData structureType of testp value
    a Fig. 1B, ipsilateral rotations at 12 weeks: GDNF (1 µg) vs PBS at 12 weeksNormal distributionOne-way ANOVA, Tukey0.006
    b Fig. 1B, ipsilateral rotations at 12 weeks: GDNF (1 µg) + CDNF (1 µg) vs PBS at 12 weeksNormal distributionOne-way ANOVA, Tukey0.0306
    c Fig. 1B, ipsilateral rotations at 12 weeks, GDNF (1 µg) + CDNF (2.5 µg) vs PBS at 12 weeksNormal distributionOne-way ANOVA, Tukey0.001
    d Fig. 1B, ipsilateral rotations at 10 weeks: CDNF (2.5 µg) vs PBS at 12 weeksNormal distributionOne-way ANOVA, Tukey0.029
    e Fig. 1D, ipsilateral rotations at 12 weeks, GDNF (2.5 µg) vs PBS at 12 weeks after lesionNormal distributionOne-way ANOVA, Tukey0.0104
    f Fig. 1D, ipsilateral rotations at 12 weeks, GDNF (2.5 µg) + CDNF (2.5 µg) vs PBS at 12 weeks after lesionNormal distributionOne-way ANOVA, Tukey0.0113
    g Fig. 2A, TH cell numbers, GDNF (1 µg) + GDNF (2.5 µg) vs VEHNormal distributionOne-way ANOVA, Tukey0.046
    h Fig. 2B, Nissl-positive cells, All NTF-treated groups differed from VEHNormal distributionOne-way ANOVA, Tukey0.0001
    i Fig. 4C, OD of pS6 staining in STR. CDNF (2.5 µg) vs GDNF (1 µg)Normal distributionOne-way ANOVA, Tukey0.0184
    j Fig. 4D, pERK-positive cells in STR. All NTF-treated groups differed from VEHNormal distributionOne-way ANOVA, Tukey0.0077
    k Fig. 5A, level of ATF6 expression in DA neuron cultures, CDNF (100 ng/ml) vs control, no factorNormal distributionOne-way ANOVA, Tukey0.04
    l Fig. 5A, level of ATF6 expression in DA neuron cultures, combination [CDNF (100 ng/ml) + GDNF (50 ng/ml)] vs controlNormal distributionOne-way ANOVA, Tukey0.0102
    m Fig. 5E, GRP78 expression, CDNF (2.5 µg) vs GDNF (1 µg)Normal distributionOne-way ANOVA, Tukey0.014
Back to top

In this issue

eneuro: 4 (1)
eNeuro
Vol. 4, Issue 1
January/February 2017
  • Table of Contents
  • Index by author
Email

Thank you for sharing this eNeuro article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Evidence for an Additive Neurorestorative Effect of Simultaneously Administered CDNF and GDNF in Hemiparkinsonian Rats: Implications for Different Mechanism of Action
(Your Name) has forwarded a page to you from eNeuro
(Your Name) thought you would be interested in this article in eNeuro.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Print
View Full Page PDF
Citation Tools
Evidence for an Additive Neurorestorative Effect of Simultaneously Administered CDNF and GDNF in Hemiparkinsonian Rats: Implications for Different Mechanism of Action
Merja H. Voutilainen, Francesca De Lorenzo, Polina Stepanova, Susanne Bäck, Li-Ying Yu, Päivi Lindholm, Eeva Pörsti, Mart Saarma, Pekka T. Männistö, Raimo K. Tuominen
eNeuro 22 February 2017, 4 (1) ENEURO.0117-16.2017; DOI: 10.1523/ENEURO.0117-16.2017

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Respond to this article
Share
Evidence for an Additive Neurorestorative Effect of Simultaneously Administered CDNF and GDNF in Hemiparkinsonian Rats: Implications for Different Mechanism of Action
Merja H. Voutilainen, Francesca De Lorenzo, Polina Stepanova, Susanne Bäck, Li-Ying Yu, Päivi Lindholm, Eeva Pörsti, Mart Saarma, Pekka T. Männistö, Raimo K. Tuominen
eNeuro 22 February 2017, 4 (1) ENEURO.0117-16.2017; DOI: 10.1523/ENEURO.0117-16.2017
Reddit logo Twitter logo Facebook logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Significance Statement
    • Introduction
    • Materials and Methods
    • Results
    • Discussion
    • Acknowledgments
    • Footnotes
    • References
    • Synthesis
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Keywords

  • 6-OHDA
  • Additive Effect
  • CDNF
  • ER stress
  • GDNF
  • rat

Responses to this article

Respond to this article

Jump to comment:

No eLetters have been published for this article.

Related Articles

Cited By...

More in this TOC Section

New Research

  • Deciding while acting - Mid-movement decisions are more strongly affected by action probability than reward amount
  • CaMKIIα promoter-controlled circuit manipulations target both pyramidal cells and inhibitory interneurons in cortical networks
  • Gas7 is a novel dendritic spine initiation factor
Show more New Research

Disorders of the Nervous System

  • Impaired AMPARs Translocation into Dendritic Spines with Motor Skill Learning in the Fragile X Mouse Model
  • Characterization of the Tau Interactome in Human Brain Reveals Isoform-Dependent Interaction with 14-3-3 Family Proteins
  • Glycolytic System in Axons Supplement Decreased ATP Levels after Axotomy of the Peripheral Nerve
Show more Disorders of the Nervous System

Subjects

  • Disorders of the Nervous System

  • Home
  • Alerts
  • Visit Society for Neuroscience on Facebook
  • Follow Society for Neuroscience on Twitter
  • Follow Society for Neuroscience on LinkedIn
  • Visit Society for Neuroscience on Youtube
  • Follow our RSS feeds

Content

  • Early Release
  • Current Issue
  • Latest Articles
  • Issue Archive
  • Blog
  • Browse by Topic

Information

  • For Authors
  • For the Media

About

  • About the Journal
  • Editorial Board
  • Privacy Policy
  • Contact
  • Feedback
(eNeuro logo)
(SfN logo)

Copyright © 2023 by the Society for Neuroscience.
eNeuro eISSN: 2373-2822

The ideas and opinions expressed in eNeuro do not necessarily reflect those of SfN or the eNeuro Editorial Board. Publication of an advertisement or other product mention in eNeuro should not be construed as an endorsement of the manufacturer’s claims. SfN does not assume any responsibility for any injury and/or damage to persons or property arising from or related to any use of any material contained in eNeuro.