Blockade of Rapid Influx of Extracellular Zn into Nigral Dopaminergic Neurons Overcomes Paraquat-Induced Parkinson's Disease in Rats

The herbicide paraquat (PQ) has been reported to enhance the risk of developing Parkinson's disease (PD) from epidemiological studies. PQ-induced reactive oxygen species (ROS) are linked with a selective loss of nigrostriatal dopaminergic neurons. Here, we first report a unique mechanism of nigrostriatal dopaminergic degeneration, in which rapid intracellular Zn dysregulation via PQ-induced ROS production causes PD in rats. When the substantia nigra pars compacta (SNpc) of rats was perfused with PQ, extracellular concentrations of glutamate and Zn were increased and decreased, respectively, in the SNpc. These changes were ameliorated by co-perfusion with Trolox, an antioxidative agent. In in vitro slice experiments, PQ rapidly increased extracellular Zn influx via AMPA receptor activation. Both loss of nigrostriatal dopaminergic neurons and increase in turning behavior in response to apomorphine were markedly reduced by coinjection of PQ and intracellular Zn chelator, i.e., ZnAF-2DA into the SNpc. Furthermore, loss of nigrostriatal dopaminergic neurons induced with a low dose of PQ, which did not induce any behavioral abnormality, was completely blocked by coinjection of ZnAF-2DA. The present study indicates that rapid influx of extracellular Zn into dopaminergic neurons via AMPA receptor activation, which is initially induced by PQ-mediated ROS production in the SNpc, induces nigrostriatal dopaminergic degeneration, resulting in PQ-induced PD in rats. Intracellular Zn dysregulation in dopaminergic neurons is the cause of PQ-induced pathogenesis in the SNpc, and the block of intracellular Zn toxicity leads to defending PQ-induced pathogenesis.