Pathological significance of converting Zn2 +dysregulation to H2O2 in AMPA-induced neurotoxicity.

The causative mechanism of nigrostriatal dopaminergic degeneration, which is a characteristic in Parkinson's disease (PD), remains to be solved, while it has been widely accepted that excessive reactive oxygen species (ROS) are the key mediator of the PD pathogenesis. In contrast, pathological significance of Zn2+-mediated ROS generation is poorly understood in the PD pathogenesis. Because one pathway of ROS generation is mitochondrial dysfunction, we focused on mitochondrial Zn2+-mediated ROS generation and examined pathological role of H2O2 signaling, which derived from mitochondrial ROS, after AMPA-induced influx of extracellular Zn2+. The increase in ROS in the mitochondria and mitochondria dysfunction were induced in the substantia nigra pars compacta (SNpc) after AMPA injection into the SNpc of rats, but not after co-injection of CaEDTA, an extracellular Zn2+ chelator, suggesting that AMPA-induced influx of extracellular Zn2+ contributes to Zn2+ dysregulation followed by ROS generation in the mitochondria and mitochondria dysfunction. Moreover, AMPA-mediated decrease in dopaminergic neurons was inhibited by co-injection of not only HYDROP, an intracellular H2O2 capturing probe, but also HYDROP-EX, an extracellular H2O2 capturing probe. The present study first indicates that AMPA-induced Zn2+ dysregulation induces mitochondria dysfunction via ROS production in the SNpc. H2O2 deriving from mitochondrial ROS is involved in dopaminergic degeneration, and H2O2 diffused to the presynapses induces postsynaptic Zn2+ dysregulation again, probably via glutamatergic excitation. It is likely that persistent H2O2 signaling induced by Zn2+ dysregulation contributes to the selective dopaminergic damage in the SNpc.