THE NEUROTOXINS OF THE DOPAMINERGIC SYSTEM: EFFECTS ON HUMAN DOPAMINERGIC NEUROBLASTOMA CELLS

Parkinson’s disease (PD) is a progressive neurodegenerative disease involving neurodegeneration of dopaminergic neurons of the substantia nigra (SN). Oxidative stress has been implicated to play a major role in the neuronal cell death associated with PD; importantly, there is a drastic depletion in cytoplasmic levels of the thiol tripeptide glutathione (GSH) within the SN of PD patients. GSH depletion has been shown to affect mitochondrial function probably via inhibition of mitochondrial complex I activity. Inhibition of complex I via systemic administration of either MPTP or rotenone give similar patterns of morphological damage as that observed in the parkinsonian brains. In vitro studies using MPP (+) ( 1-Methyl-4-phenylpyridinium ion, the active metabolite of MPTP)- or rotenone- induced cell death were performed to test the potential neuroprotective effects of GSH and N-acetylcysteine (NAC). We investigated the effect of MPP (+) or rotenone on viability, GSH levels, mitochondrial respiratory chain complex I activity and ATP production in human dopaminergic SH-SY5Y cells. We found that MPP (+) and rotenone dose- and time- dependently altered SH-SY5Y cell viability associated with a decreased of GSH levels, complex I activity and ATP production. We observed a protective effect of GSH and NAC on SH-SY5Y cells against MPP (+) and rotenone indicating these compounds as potential agents in prevention of neuronal degeneration in PD. These models will be useful tool to further study in exploring the molecular mechanism for thiol-based compound-mediated cytopotection of dopaminergic neurons. Supported by the University of Bologna, Funds for Selected Research Topics.