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The Journal of Neuroscience, July 29, 2009, 29(30):9651-9659; doi:10.1523/JNEUROSCI.0833-09.2009

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 Previous Article

Cellular/Molecular
Mesencephalic Astrocyte-Derived Neurotrophic Factor Is Neurorestorative in Rat Model of Parkinson's Disease

Merja H. Voutilainen,¹ Susanne Bäck,¹ Eeva Pörsti,¹ Liisa Toppinen,¹ Lauri Lindgren,¹ Päivi Lindholm,² Johan Peränen,² Mart Saarma,² and Raimo K. Tuominen¹

¹Division of Pharmacology and Toxicology, Faculty of Pharmacy, and ²Institute of Biotechnology, Viikki Biocenter, University of Helsinki, FIN-00014 Helsinki, Finland

Correspondence should be addressed to Dr. Mart Saarma, Institute of Biotechnology, P.O. Box 56, Viikki Biocenter, University of Helsinki, FIN-00014 Helsinki, Finland. Email: mart.saarma{at}helsinki.fi

Neurotrophic factors are promising candidates for the treatment of Parkinson's disease (PD). Mesencephalic astrocyte-derived neurotrophic factor (MANF) belongs to a novel evolutionarily conserved family of neurotrophic factors. We examined whether MANF has neuroprotective and neurorestorative effect in an experimental model of PD in rats. We also studied the distribution and transportation of intrastriatally injected MANF in the brain and compared it with glial cell line-derived neurotrophic factor (GDNF). Unilateral lesion of nigrostriatal dopaminergic system was induced by intrastriatal injection of 6-hydroxydopamine (6-OHDA). Amphetamine-induced turning behavior was monitored up to 12 weeks after the unilateral lesion. The local diffusion at the injection site and transportation profiles of intrastriatally injected MANF and GDNF were studied by immunohistochemical detection of the unlabeled growth factors as well as by autoradiographic and gamma counting detection of ¹²⁵I-labeled trophic factors. Intrastriatally injected MANF protected nigrostriatal dopaminergic nerves from 6-OHDA-induced degeneration as evaluated by counting tyrosine hydroxylase (TH)-positive cell bodies in the substantia nigra (SN) and TH-positive fibers in the striatum. More importantly, MANF also restored the function of the nigrostriatal dopaminergic system when administered either 6 h before or 4 weeks after 6-OHDA administration in the striatum. MANF was distributed throughout the striatum more readily than GDNF. The mechanism of MANF action differs from that of GDNF because intrastriatally injected ¹²⁵I-MANF was transported to the frontal cortex, whereas ¹²⁵I-GDNF was transported to the SN. Our results suggest that MANF is readily distributed throughout the striatum and has significant therapeutic potential for the treatment of PD.

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Received Feb. 18, 2009; revised May 29, 2009; accepted June 10, 2009.

Correspondence should be addressed to Dr. Mart Saarma, Institute of Biotechnology, P.O. Box 56, Viikki Biocenter, University of Helsinki, FIN-00014 Helsinki, Finland. Email: mart.saarma{at}helsinki.fi

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