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.

MPTP produces clinical, biochemical, and neuropathologic changes reminiscent of those that occur in idiopathic Parkinson's disease (PD). In the present study we show that MPTP treatment led to activation of microglia in the substantia nigra pars compacta (SNpc), which was associated and colocalized with an increase in inducible nitric oxide synthase (iNOS) expression. In iNOS-deficient mice the increase of iNOS expression but not the activation of microglia was blocked. Dopaminergic SNpc neurons of iNOS-deficient mice were almost completely protected from MPTP toxicity in a chronic paradigm of MPTP toxicity. Because the MPTP-induced decrease in striatal concentrations of dopamine and its metabolites did not differ between iNOS-deficient mice and their wild-type littermates, this protection was not associated with a preservation of nigrostriatal terminals. Our results suggest that iNOS-derived nitric oxide produced in microglia plays an important role in the death of dopaminergic neurons but that other mechanisms contribute to the loss of dopaminergic terminals in MPTP neurotoxicity. We conclude that inhibition of iNOS may be a promising target for the treatment of PD. Key Words: MPTP-Nitric oxide synthase-Microglia-Parkinson's disease-Free radicalsInflammation.

Environmental and genetic factors that contribute to the pathogenesis of Parkinson's disease are discussed. Mutations in the a-synuclein (aSYN ) gene are associated with rare cases of autosomal-dominant Parkinson's disease. We have analysed the dopaminergic system in transgenic mouse lines that expressed mutant [A30P]aSYN under the control of a neurone-speci®c Thy-1 or a tyrosine hydroxylase (TH) promoter. The latter mice showed somal and neuritic accumulation of transgenic [A30P]aSYN in TH-positive neurones in the substantia nigra. However, there was no difference in the number of TH-positive neurones in the substantia nigra and the concentrations of catecholamines in the striatum between these transgenic mice and non-transgenic littermates. To investigate whether forced expression of [A30P]aSYN increased the sensitivity to putative environmental factors we subjected transgenic mice to a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) regimen. The MPTPinduced decrease in the number of TH-positive neurones in the substantia nigra and the concentrations of catecholamines in the striatum did not differ in any of the [A30P]aSYN transgenic mouse lines compared with wild-type controls. These results suggest that mutations and forced expression of aSYN are not likely to increase the susceptibility to environmental toxins in vivo.

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