Is there a rationale for neuroprotection against dopamine toxicity in Parkinson's disease?

Parkinson's disease is a progressive neurological disease caused by rather selective degeneration of the dopaminergic neurons in the substantia nigra. Though subject to intensive research, the etiology of this nigral loss is still undetermined and treatment is basically symptomatic. The current major hypothesis is that nigral neuronal death in PD is due to excessive oxidative stress generated by auto and enzymatic oxidation of the endogenous neurotransmitter dopamine (DA), the formation of neuromelanin (NM) and the presence of a high concentration of iron. In this review article although we concisely describe the effects of NM and iron on neuronal survival, we mainly focus on the molecular mechanisms of DA-induced apoptosis. DA exerts its toxic effects through its oxidative metabolites either in vitro or in vivo The oxidative metabolites then activate a very intricate web of signals, which culminate in cell death. The signal transduction pathways and genes, which are associated with DA toxicity are described in detail.