Extracellular dopamine induces the oxidative toxicity of SH-SY5Y cells.

Dopamine-induced neuronal cytotoxicity has been proposed as a leading pathological mechanism underlying many neuronal degenerative disorders including Parkinson disease. Various hypotheses have been proposed including oxidative stress and dopamine (DA)-induced intracellular signal disorder via DA D1 and D2 receptors. The exact mechanism involved in this process is far from clear. In this study, employing a neuronal blastoma cell line, SH-SY5Y, we tried to elucidate the roles of these different suggested mechanisms in this pathological process. The results showed that DA induced cell toxicity in a dose- and time-dependent way. Selective D1 and D2 DA receptor antagonist could not block the cytotoxic effects, whereas reductive reagent ascorbic acid but not GSH could effectively rescue the cell death, suggesting that DA-induced cell toxicity was caused by an extracellular oxidative stress. This was further supported by the enhancing effects of DA transporter blocker, GBR, which could increase the cell death when pretreated. Finally, ascorbic acid could also protect SY5Y cells from DA-induced cellular apoptotic signal changes including PARP and P53. Our studies suggested that DA exerted its cytotoxic effects via an extracellular metabolism, whereas intracellular transportation could reduce its oxidative stress. Cytotoxicity effects induced by extracellular DA could be protected by reductive agents as ascorbic acid. These results help to broaden our understanding of the mechanisms of DA-induced cell death and may provide potentially therapeutical alternative for the neurodegenerative disorders. Copyright 2008 Wiley-Liss, Inc.