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

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Voutilainen , M H , De Lorenzo , F , Stepanova , P , Bäck , S , Pulkkila , P , Pörsti , E , Saarma , M , Männistö , P T & Tuominen , R K 2017 , ' Evidence for an Additive Neurorestorative Effect of Simultaneously Administered CDNF and GDNF in Hemiparkinsonian Rats: Implications for Different Mechanism of Action ' , eNeuro , vol. 4 , no. 1 , e0117-16.2017 . https://doi.org/10.1523/ENEURO.0117-16.2017

Title: Evidence for an Additive Neurorestorative Effect of Simultaneously Administered CDNF and GDNF in Hemiparkinsonian Rats: Implications for Different Mechanism of Action
Author: Voutilainen, Merja H.; De Lorenzo, Francesca; Stepanova, Polina; Bäck, Susanne; Pulkkila, Päivi; Pörsti, Eeva; Saarma, Mart; Männistö, Pekka T.; Tuominen, Raimo K.
Contributor: University of Helsinki, Institute of Biotechnology
University of Helsinki, Institute of Biotechnology
University of Helsinki, Institute of Biotechnology
University of Helsinki, Faculty of Pharmacy
University of Helsinki, Institute of Biotechnology
University of Helsinki, Institute of Biotechnology
University of Helsinki, Faculty of Pharmacy
University of Helsinki, Faculty of Pharmacy
Date: 2017
Language: eng
Number of pages: 14
Belongs to series: eNeuro
ISSN: 2373-2822
URI: http://hdl.handle.net/10138/228730
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).
Subject: 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
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