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.
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.
Eberhardt
O
O
Neurodegeneration, Neuroregeneration, and Neurooncology Laboratories, Department of Neurology, University of Tübingen, 72076 Tübingen, Germany.
Coelln
R V
RV
Kugler
S
S
Lindenau
J
J
Rathke-Hartlieb
S
S
Gerhardt
E
E
Haid
S
S
Isenmann
S
S
Gravel
C
C
Srinivasan
A
A
Bahr
M
M
Weller
M
M
Dichgans
J
J
Schulz
J B
JB
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D061945:Caspase Inhibitors; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics / Q000494:pharmacology; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000378:metabolism / Q000628:therapy*; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism; D011506:Proteins / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051636:X-Linked Inhibitor of Apoptosis Protein
D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; C495039:GDNF protein, human; C495040:Gdnf protein, mouse; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D011506:Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D004298:Dopamine