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

O Eberhardt; R V Coelln; S Kugler; J Lindenau; S Rathke-Hartlieb; E Gerhardt; S Haid; S Isenmann; C Gravel; A Srinivasan; M Bahr; M Weller; J Dichgans; J B Schulz

doi:10.1523/JNEUROSCI.20-24-09126.2000

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

J Neurosci. 2000 Dec 15;20(24):9126-34. doi: 10.1523/JNEUROSCI.20-24-09126.2000.

Authors

O Eberhardt¹, R V Coelln, S Kugler, J Lindenau, S Rathke-Hartlieb, E Gerhardt, S Haid, S Isenmann, C Gravel, A Srinivasan, M Bahr, M Weller, J Dichgans, J B Schulz

Affiliation

¹ Neurodegeneration, Neuroregeneration, and Neurooncology Laboratories, Department of Neurology, University of Tübingen, 72076 Tübingen, Germany.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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-Linked Inhibitor of Apoptosis Protein

Substances

Caspase Inhibitors
Enzyme Inhibitors
GDNF protein, human
Gdnf protein, mouse
Gdnf protein, rat
Glial Cell Line-Derived Neurotrophic Factor
Nerve Growth Factors
Nerve Tissue Proteins
Proteins
X-Linked Inhibitor of Apoptosis Protein
XIAP protein, human
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Dopamine