The roles of the thioredoxin system and peroxiredoxins in 1-methyl-4-phenyl-pyridinium ion-induced cytotoxicity in rat pheochromocytoma cells

The 1-methyl-4-phenyl-pyridinium ion (MPP⁺), an active metabolite of the neurotoxin, N-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP), induces death in rat pheochromocytoma (PC12) cells, suggesting a cell model of Parkinson's disease (PD). However, most of the toxic mechanisms remain illusive. In this study, we have found that MPP⁺ induced apoptotic cell death in PC12 cells as measured by the MTT assay and annexin V-FITC staining. Besides, MPP⁺ also resulted in decreased mitochondrial membrane potential and increased mitochondrial free radical formation as imaged by the staining of TMRE or MitoSOX, respectively, confirming the neurotoxic effect of MPP⁺ by interfering with mitochondrial functions. Western blot analysis indicated that MPP⁺ differentially regulated the expressions and over-oxidation of thioredoxin systems and peroxiredoxins. Since these enzymes are known to prevent oxidative stress and apoptosis, these evidences could be regarded as a novel neurotoxic mechanism of MPP⁺ and also provide an alternative view of developing drug therapies for PD.