Rescue from death but not from functional impairment: caspase inhibition protects dopaminergic cells against 6-hydroxydopamine-induced apoptosis but not against the loss of their terminals

Despite the identification of several mutations in familial Parkinson's dis ease (PD), the underlying mechanisms of dopaminergic neuronal loss in idiop athic PD are still unknown. To study whether caspase-dependent apoptosis ma y play a role in the pathogenesis of PD, we examined 6-hydroxydopamine (6-O HDA) toxicity in dopaminergic SH-SY5Y cells and in embryonic dopaminergic m esencephalic cultures. 6-OHDA induced activation of caspases 3, 6 and 9, ch romatin condensation and cell death in SH-SY5Y cells. The caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-(O-methyl)fluoromethylketone (zVAD-fmk) or a denovirally mediated ectopic expression of the X-chromosomal inhibitor of a poptosis protein (XIAP) blocked caspase activation and prevented death of S H-SY5Y cells. Similarly, zVAD-fmk provided protection from 6-OHDA-induced l oss of tyrosine hydroxylase-positive neurones in mesencephalic cultures. In contrast, zVAD-fmk failed to protect mesencephalic dopaminergic neurones f rom-6-OHDA-induced loss of neurites and reduction of [H-3]dopamine uptake. These data suggest that, although caspase inhibition provides protection fr om 6-OHDA-induced death of dopaminergic neurones, the neurones may remain f unctionally impaired.