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

Research output: Contribution to journalArticleScientificpeer-review

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder associated with a progressive loss of dopaminergic (DAergic) neurons of the substantia nigra (SN) and the accumulation of intracellular inclusions containing alpha-synuclein. Current therapies do not stop the progression of the disease, and the efficacy of these treatments wanes over time. Neurotrophic factors (NTFs) are naturally occurring proteins promoting the survival and differentiation of neurons and the maintenance of neuronal contacts. CDNF (cerebral dopamine NTF) and GDNF (glial cell line-derived NTF) are able to protect DAergic neurons against toxin-induced degeneration in experimental models of PD. Here, we report an additive neurorestorative effect of coadministration of CDNF and GDNF in the unilateral 6-hydroxydopamine (6-OHDA) lesion model of PD in rats. NTFs were given into the striatum four weeks after unilateral intrastriatal injection of 6-OHDA (20 mu g). Amphetamine-induced (2.5 mg/kg, i.p.) rotational behavior was measured every two weeks. Number of tyrosine hydroxylase (TH)-positive cells from SN pars compacta (SNpc) and density of TH-positive fibers in the striatum were analyzed at 12 weeks after lesion. CDNF and GDNF alone restored the DAergic function, and one specific dose combination had an additive effect: CDNF (2.5 mu g) and GDNF (1 mu g) coadministration led to a stronger trophic effect relative to either of the single treatments alone. The additive effect may indicate different mechanism of action for the NTFs. Indeed, both NTFs activated the survival promoting PI3 kinase (PI3K)-Akt signaling pathway, but only CDNF decreased the expression level of tested endoplasmatic reticulum (ER) stress markers ATF6, glucose-regulated protein 78 (GRP78), and phosphorylation of eukaryotic initiation factor 2 alpha subunit (eIF2 alpha).
Original languageEnglish
Article numbere0117-16.2017
JournaleNeuro
Volume4
Issue number1
Number of pages14
ISSN2373-2822
DOIs
Publication statusPublished - 2017
MoE publication typeA1 Journal article-refereed

Fields of Science

  • 317 Pharmacy
  • 3112 Neurosciences
  • 6-OHDA
  • additive effect
  • CDNF
  • ER stress
  • rat
  • ENDOPLASMIC-RETICULUM STRESS
  • NEUROTROPHIC FACTOR GDNF
  • MIDBRAIN DOPAMINE NEURONS
  • ADHESION MOLECULE NCAM
  • PARKINSONS-DISEASE
  • IN-VIVO
  • CDNF/MANF FAMILY
  • TYROSINE-HYDROXYLASE
  • SUBSTANTIA-NIGRA
  • GENE-THERAPY

Cite this

@article{15ad22e9bbda43e48d2ddbe4b24af49b,
title = "Evidence for an Additive Neurorestorative Effect of Simultaneously Administered CDNF and GDNF in Hemiparkinsonian Rats: Implications for Different Mechanism of Action",
abstract = "Parkinson's disease (PD) is a neurodegenerative disorder associated with a progressive loss of dopaminergic (DAergic) neurons of the substantia nigra (SN) and the accumulation of intracellular inclusions containing alpha-synuclein. Current therapies do not stop the progression of the disease, and the efficacy of these treatments wanes over time. Neurotrophic factors (NTFs) are naturally occurring proteins promoting the survival and differentiation of neurons and the maintenance of neuronal contacts. CDNF (cerebral dopamine NTF) and GDNF (glial cell line-derived NTF) are able to protect DAergic neurons against toxin-induced degeneration in experimental models of PD. Here, we report an additive neurorestorative effect of coadministration of CDNF and GDNF in the unilateral 6-hydroxydopamine (6-OHDA) lesion model of PD in rats. NTFs were given into the striatum four weeks after unilateral intrastriatal injection of 6-OHDA (20 mu g). Amphetamine-induced (2.5 mg/kg, i.p.) rotational behavior was measured every two weeks. Number of tyrosine hydroxylase (TH)-positive cells from SN pars compacta (SNpc) and density of TH-positive fibers in the striatum were analyzed at 12 weeks after lesion. CDNF and GDNF alone restored the DAergic function, and one specific dose combination had an additive effect: CDNF (2.5 mu g) and GDNF (1 mu g) coadministration led to a stronger trophic effect relative to either of the single treatments alone. The additive effect may indicate different mechanism of action for the NTFs. Indeed, both NTFs activated the survival promoting PI3 kinase (PI3K)-Akt signaling pathway, but only CDNF decreased the expression level of tested endoplasmatic reticulum (ER) stress markers ATF6, glucose-regulated protein 78 (GRP78), and phosphorylation of eukaryotic initiation factor 2 alpha subunit (eIF2 alpha).",
keywords = "317 Pharmacy, 3112 Neurosciences, 6-OHDA , additive effect, CDNF, ER stress, rat, ENDOPLASMIC-RETICULUM STRESS , NEUROTROPHIC FACTOR GDNF , MIDBRAIN DOPAMINE NEURONS , ADHESION MOLECULE NCAM , PARKINSONS-DISEASE , IN-VIVO , CDNF/MANF FAMILY , TYROSINE-HYDROXYLASE , SUBSTANTIA-NIGRA , GENE-THERAPY",
author = "Voutilainen, {Merja H.} and {De Lorenzo}, Francesca and Polina Stepanova and Susanne B{\"a}ck and P{\"a}ivi Pulkkila and Eeva P{\"o}rsti and Mart Saarma and M{\"a}nnist{\"o}, {Pekka T.} and Tuominen, {Raimo K.}",
year = "2017",
doi = "10.1523/ENEURO.0117-16.2017",
language = "English",
volume = "4",
journal = "eNeuro",
issn = "2373-2822",
publisher = "Society of Neuroscience",
number = "1",

}

TY - JOUR

T1 - Evidence for an Additive Neurorestorative Effect of Simultaneously Administered CDNF and GDNF in Hemiparkinsonian Rats: Implications for Different Mechanism of Action

AU - Voutilainen, Merja H.

AU - De Lorenzo, Francesca

AU - Stepanova, Polina

AU - Bäck, Susanne

AU - Pulkkila, Päivi

AU - Pörsti, Eeva

AU - Saarma, Mart

AU - Männistö, Pekka T.

AU - Tuominen, Raimo K.

PY - 2017

Y1 - 2017

N2 - Parkinson's disease (PD) is a neurodegenerative disorder associated with a progressive loss of dopaminergic (DAergic) neurons of the substantia nigra (SN) and the accumulation of intracellular inclusions containing alpha-synuclein. Current therapies do not stop the progression of the disease, and the efficacy of these treatments wanes over time. Neurotrophic factors (NTFs) are naturally occurring proteins promoting the survival and differentiation of neurons and the maintenance of neuronal contacts. CDNF (cerebral dopamine NTF) and GDNF (glial cell line-derived NTF) are able to protect DAergic neurons against toxin-induced degeneration in experimental models of PD. Here, we report an additive neurorestorative effect of coadministration of CDNF and GDNF in the unilateral 6-hydroxydopamine (6-OHDA) lesion model of PD in rats. NTFs were given into the striatum four weeks after unilateral intrastriatal injection of 6-OHDA (20 mu g). Amphetamine-induced (2.5 mg/kg, i.p.) rotational behavior was measured every two weeks. Number of tyrosine hydroxylase (TH)-positive cells from SN pars compacta (SNpc) and density of TH-positive fibers in the striatum were analyzed at 12 weeks after lesion. CDNF and GDNF alone restored the DAergic function, and one specific dose combination had an additive effect: CDNF (2.5 mu g) and GDNF (1 mu g) coadministration led to a stronger trophic effect relative to either of the single treatments alone. The additive effect may indicate different mechanism of action for the NTFs. Indeed, both NTFs activated the survival promoting PI3 kinase (PI3K)-Akt signaling pathway, but only CDNF decreased the expression level of tested endoplasmatic reticulum (ER) stress markers ATF6, glucose-regulated protein 78 (GRP78), and phosphorylation of eukaryotic initiation factor 2 alpha subunit (eIF2 alpha).

AB - Parkinson's disease (PD) is a neurodegenerative disorder associated with a progressive loss of dopaminergic (DAergic) neurons of the substantia nigra (SN) and the accumulation of intracellular inclusions containing alpha-synuclein. Current therapies do not stop the progression of the disease, and the efficacy of these treatments wanes over time. Neurotrophic factors (NTFs) are naturally occurring proteins promoting the survival and differentiation of neurons and the maintenance of neuronal contacts. CDNF (cerebral dopamine NTF) and GDNF (glial cell line-derived NTF) are able to protect DAergic neurons against toxin-induced degeneration in experimental models of PD. Here, we report an additive neurorestorative effect of coadministration of CDNF and GDNF in the unilateral 6-hydroxydopamine (6-OHDA) lesion model of PD in rats. NTFs were given into the striatum four weeks after unilateral intrastriatal injection of 6-OHDA (20 mu g). Amphetamine-induced (2.5 mg/kg, i.p.) rotational behavior was measured every two weeks. Number of tyrosine hydroxylase (TH)-positive cells from SN pars compacta (SNpc) and density of TH-positive fibers in the striatum were analyzed at 12 weeks after lesion. CDNF and GDNF alone restored the DAergic function, and one specific dose combination had an additive effect: CDNF (2.5 mu g) and GDNF (1 mu g) coadministration led to a stronger trophic effect relative to either of the single treatments alone. The additive effect may indicate different mechanism of action for the NTFs. Indeed, both NTFs activated the survival promoting PI3 kinase (PI3K)-Akt signaling pathway, but only CDNF decreased the expression level of tested endoplasmatic reticulum (ER) stress markers ATF6, glucose-regulated protein 78 (GRP78), and phosphorylation of eukaryotic initiation factor 2 alpha subunit (eIF2 alpha).

KW - 317 Pharmacy

KW - 3112 Neurosciences

KW - 6-OHDA

KW - additive effect

KW - CDNF

KW - ER stress

KW - rat

KW - ENDOPLASMIC-RETICULUM STRESS

KW - NEUROTROPHIC FACTOR GDNF

KW - MIDBRAIN DOPAMINE NEURONS

KW - ADHESION MOLECULE NCAM

KW - PARKINSONS-DISEASE

KW - IN-VIVO

KW - CDNF/MANF FAMILY

KW - TYROSINE-HYDROXYLASE

KW - SUBSTANTIA-NIGRA

KW - GENE-THERAPY

U2 - 10.1523/ENEURO.0117-16.2017

DO - 10.1523/ENEURO.0117-16.2017

M3 - Article

VL - 4

JO - eNeuro

JF - eNeuro

SN - 2373-2822

IS - 1

M1 - e0117-16.2017

ER -