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

• Published in: The Journal of neuroscience Vol. 20; no. 24; pp. 9126 - 9134
• Main Authors: Eberhardt, Olaf, Coelln, Rainer V, Kugler, Sebastian, Lindenau, Jorg, Rathke-Hartlieb, Silvia, Gerhardt, Ellen, Haid, Sibylle, Isenmann, Stefan, Gravel, Claude, Srinivasan, Anu, Bahr, Mathias, Weller, Michael, Dichgans, Johannes, Schulz, Jorg B
• Format: Journal Article
• Language: English
• Published: United States Soc Neuroscience 15.12.2000; Society for Neuroscience
• Subjects: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Adenoviridae - genetics; Animals; Apoptosis - drug effects; Caspase Inhibitors; Cells, Cultured; Dopamine - metabolism; Drug Synergism; Enzyme Inhibitors - pharmacology; Gene Transfer Techniques; Genetic Therapy - methods; Genetic Vectors - genetics; Genetic Vectors - pharmacology; Glial Cell Line-Derived Neurotrophic Factor; Humans; Male; Mice; Mice, Inbred C57BL; Nerve Growth Factors; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Nerve Tissue Proteins - pharmacology; Parkinson Disease, Secondary - chemically induced; Parkinson Disease, Secondary - metabolism; Parkinson Disease, Secondary - therapy; Presynaptic Terminals - drug effects; Presynaptic Terminals - metabolism; Proteins - genetics; Proteins - metabolism; Proteins - pharmacology; Rats; Rats, Sprague-Dawley; Substantia Nigra - drug effects; Substantia Nigra - metabolism; Substantia Nigra - pathology; X-chromosome-linked inhibitor of apoptosis; X-Linked Inhibitor of Apoptosis Protein
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/jneurosci.20-24-09126.2000

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.