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

被引:0
作者
Eberhardt, O
Coelln, RV
Kügler, S
Lindenau, J
Rathke-Hartlieb, S
Gerhardt, E
Haid, S
Isenmann, S
Gravel, C
Srinivasan, A
Bähr, M
Weller, M
Dichgans, J
Schulz, JB
机构
[1] Univ Tubingen, Dept Neurol, Neurodegenerat Lab, D-72076 Tubingen, Germany
[2] Univ Tubingen, Dept Neurol, Neuroregenerat Lab, D-72076 Tubingen, Germany
[3] Univ Tubingen, Dept Neurol, Neurooncol Lab, D-72076 Tubingen, Germany
[4] Idun Pharmaceut Inc, La Jolla, CA 92037 USA
[5] Univ Laval Robert Giffard, Ctr Rech, Quebec City, PQ G1H 5Y8, Canada
关键词
Parkinson's disease; apoptosis; caspases; gene therapy; X-chromosome-linked inhibitor of apoptosis; glial cell line-derived neurotrophic factor;
D O I
暂无
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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-benzyloxycarbonyl- 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.
引用
收藏
页码:9126 / 9134
页数:9
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