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, bioc hemical, and neuropathological changes reminiscent of those occurring in id iopathic Parkinson's disease (PD). Here we show that a peptide caspase inhi bitor, N-benzyloxycarbonyl- val-ala-asp-fluoromethyl ketone, or adenoviral gene transfer (AdV) of a protein caspase inhibitor, X-chromosome-linked inh ibitor of apoptosis (XIAP), prevent cell death of dopaminergic substantia n igra 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 no t differ between AdV-XIAP- and control vector-treated mice, this protection is not associated with a preservation of nigrostriatal terminals. In contr ast, the combination of adenoviral gene transfer of XIAP and of the glial c ell line-derived neurotrophic factor to the striatum provides synergistic e ffects, rescuing dopaminergic SNpc neurons from cell death and maintaining their nigrostriatal terminals. These data suggest that a combination of a c aspase inhibitor, which blocks death, and a neurotrophic factor, which prom otes the specific function of the rescued neurons, may be a promising strat egy for the treatment of PD.