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 α-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 µg). 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 (2.5µg) and GDNF (1µg) 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 2α subunit (eIF2α).
authors.affiliation: Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, Viikki Biocenter, University of Helsinki, FIN-00014 Helsinki, Finland; Institute of Biotechnology, Viikki Biocenter, University of Helsinki, FIN-00014 Helsinki, Finland.
authors.forename: Merja H
authors.identifier: 0000-0002-9832-7655
authors.initials: MH
authors.lastname: Voutilainen
authors.affiliation: Institute of Biotechnology, Viikki Biocenter, University of Helsinki , FIN-00014 Helsinki, Finland.
authors.forename: Francesca
authors.initials: F
authors.lastname: De Lorenzo
authors.affiliation: Institute of Biotechnology, Viikki Biocenter, University of Helsinki , FIN-00014 Helsinki, Finland.
authors.forename: Polina
authors.initials: P
authors.lastname: Stepanova
authors.affiliation: Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, Viikki Biocenter, University of Helsinki , FIN-00014 Helsinki, Finland.
authors.forename: Susanne
authors.initials: S
authors.lastname: Bäck
authors.affiliation: Institute of Biotechnology, Viikki Biocenter, University of Helsinki , FIN-00014 Helsinki, Finland.
authors.forename: Li-Ying
authors.initials: LY
authors.lastname: Yu
authors.affiliation: Institute of Biotechnology, Viikki Biocenter, University of Helsinki , FIN-00014 Helsinki, Finland.
authors.forename: Päivi
authors.identifier: 0000-0003-3022-5035
authors.initials: P
authors.lastname: Lindholm
authors.affiliation: Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, Viikki Biocenter, University of Helsinki , FIN-00014 Helsinki, Finland.
authors.forename: Eeva
authors.initials: E
authors.lastname: Pörsti
authors.affiliation: Institute of Biotechnology, Viikki Biocenter, University of Helsinki , FIN-00014 Helsinki, Finland.
authors.forename: Mart
authors.identifier: 0000-0001-5543-7160
authors.initials: M
authors.lastname: Saarma
authors.affiliation: Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, Viikki Biocenter, University of Helsinki , FIN-00014 Helsinki, Finland.
authors.forename: Pekka T
authors.initials: PT
authors.lastname: Männistö
authors.affiliation: Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, Viikki Biocenter, University of Helsinki , FIN-00014 Helsinki, Finland.
authors.forename: Raimo K
authors.initials: RK
authors.lastname: Tuominen
mesh_terms: D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage*; D002478:Cells, Cultured; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D000091342:Endoplasmic Reticulum Chaperone BiP; D007839:Functional Laterality; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009414:Nerve Growth Factors / Q000008:administration & dosage*; D018696:Neuroprotective Agents / Q000008:administration & dosage; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D065842:Pars Compacta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000008:administration & dosage; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D000978:Antiparkinson Agents; C522217:CDNF protein, human; D000697:Central Nervous System Stimulants; D000091342:Endoplasmic Reticulum Chaperone BiP; D051100:Glial Cell Line-Derived Neurotrophic Factor; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D011994:Recombinant Proteins; D016627:Oxidopamine; D000661:Amphetamine; D014446:Tyrosine 3-Monooxygenase
keywords: 6-OHDA; CDNF; ER stress; GDNF; additive effect; rat