Evidence for an Additive Neurorestorative Effect of Simultaneously Administered CDNF and GDNF in Hemiparkinsonian Rats: Implications for Different Mechanism of Action
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 t...
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Published in | eNeuro Vol. 4; no. 1; p. ENEURO.0117-16.2017 |
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Main Authors | , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Society for Neuroscience
01.01.2017
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Subjects | |
Online Access | Get full text |
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Summary: | 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). |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 F.D.L. and P.S. contributed equally to this work. S. Bäck’s present address: National Institute on Drug Abuse, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD 21224. MHV, PL, MS and RKT are inventors of the CDNF-patent, which is owned by Herantis Pharma Plc. MS is a shareholder of Herantis Pharma Plc. The study was supported by grants from the Jane and Aatos Erkko Foundation, Michael J. Fox Foundation for Parkinson’s Research, Eu-ERA-NET, Sigrid Jusélius Foundation, and the Academy of Finland. M.H.V. was supported by grants from the Finnish Cultural Foundation and Finnish Parkinson Foundation. Author contributions: M.H.V., S.B., M.S., P.T.M., and R.K.T. designed research; M.H.V., F.D.L., P.S., S.B., L.Y., P.L., and E.P. performed research; M.H.V., F.D.L., P.S., S.B., L.Y., P.L., and E.P. analyzed data; M.H.V., M.S., P.T.M., and R.K.T. wrote the paper. |
ISSN: | 2373-2822 2373-2822 |
DOI: | 10.1523/ENEURO.0117-16.2017 |