Synergistic effects of dopamine and Zn2+ on the induction of PC12 cell death and dopamine depletion in the striatum: possible implication in the pathogenesis of Parkinson's disease.

The mechanism that underlies the progressive degeneration of the dopaminergic neurons in Parkinson's disease (PD) is not clear. The Zn(2+) level in the substantia nigra of Parkinson's patients is increased. However, it is unknown whether Zn(2+) has a role in the degeneration of dopaminergic neurons. This study identifies an interaction between dopamine and Zn(2+) that induces cell death. When PC12 cells were pretreated with Zn(2+) before dopamine treatment, dopamine and Zn(2+) synergistically increased cell death, while Zn(2+) and H(2)O(2) had only additive effects on cell death. The synergistic effect appeared to be caused by increased apoptosis rather than necrosis. The synergistic effect was specific for Zn(2+). The synergistic effect was inhibited by thiol antioxidants but was not significantly affected by calcium channel blockers. There is a similar synergistic effect when dopamine and Zn(2+) were coinfused into the striatum, resulting in striatal dopamine content depletion in vivo. Thus, both dopamine oxidation and Zn(2+) are possibly linked to the degeneration of dopaminergic neurons.