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The Journal of Neuroscience, December 15, 2000, 20(24):9126-9134
Protection by Synergistic Effects of Adenovirus-Mediated X-Chromosome-Linked Inhibitor of Apoptosis and Glial Cell Line-Derived Neurotrophic Factor Gene Transfer in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Model of Parkinson's Disease
Olaf Eberhardt1, Rainer V. Coelln1, Sebastian Kügler2, Jörg Lindenau1, Silvia Rathke-Hartlieb1, Ellen Gerhardt1, Sibylle Haid1, Stefan Isenmann2, Claude Gravel4, Anu Srinivasan5, Mathias Bähr2, Michael Weller3, Johannes Dichgans1, 2, 3, and Jörg B. Schulz1 1 Neurodegeneration, 2 Neuroregeneration, and 3 Neurooncology Laboratories, Department of Neurology, University of Tübingen, 72076 Tübingen, Germany, 4 Centre de Recherche Université Laval Robert-Giffard, Beauport, Québec, Canada G1H 5Y8, and 5 Idun Pharmaceuticals Inc., La Jolla, California 92037
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces clinical, biochemical, and neuropathological changes reminiscent of those occurring in idiopathic Parkinson's disease (PD). Here we show that a peptide caspase inhibitor, N-benzyloxy-carbonyl-val-ala-asp-fluoromethyl ketone, or adenoviral gene transfer (AdV) of a protein caspase inhibitor, X-chromosome-linked inhibitor of apoptosis (XIAP), prevent cell death of dopaminergic substantia nigra pars compacta (SNpc) neurons induced by MPTP or its active metabolite 1-methyl-4-phenylpyridinium in vitro and in vivo. Because the MPTP-induced decrease in striatal concentrations of dopamine and its metabolites does not differ between AdV-XIAP- and control vector-treated mice, this protection is not associated with a preservation of nigrostriatal terminals. In contrast, the combination of adenoviral gene transfer of XIAP and of the glial cell line-derived neurotrophic factor to the striatum provides synergistic effects, rescuing dopaminergic SNpc neurons from cell death and maintaining their nigrostriatal terminals. These data suggest that a combination of a caspase inhibitor, which blocks death, and a neurotrophic factor, which promotes the specific function of the rescued neurons, may be a promising strategy for the treatment of PD.
Key words: Parkinson's disease; apoptosis; caspases; gene therapy; X-chromosome-linked inhibitor of apoptosis; glial cell line-derived neurotrophic factor
Copyright © 2000 Society for Neuroscience 0270-6474/00/20249126-09$05.00/0
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