Iron-enhanced paraquat-mediated dopaminergic cell death due to increased oxidative stress as a consequence of microglial activation.

Environmental paraquat and neonatal iron exposure have both separately been suggested as potential risk factors for sporadic forms of Parkinson's disease (PD). In this study, we demonstrate that combined environmental exposure to these two agents results in modulations in microglial activation state. Apocynin, an NADPH oxidase inhibitor, was found to attenuate the release of superoxide from microglia stimulated by combined paraquat and iron and blocked paraquat-induced dopaminergic neuronal death. Furthermore, pretreatment with the synthetic superoxide dismutase/catalase mimetic, EUK-189, significantly decreased microglial activation mediated by combined paraquat and iron treatment. These findings support the notion that environmental PD risk factors may act synergetically to produce neurodegeneration associated with the disorder and that iron and paraquat may act via common oxidative stress-mediated mechanism involving microglial activation.