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.
Chen
Victor T K
VT
Department of Surgery, Cardinal Tien Hospital, Hsintien, Taipei County, Taiwan.
Huang
Chuen-Lin
CL
Lee
Yi-Chao
YC
Liao
Wei-Chen
WC
Huang
Nai-Kuei
NK
D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015227:Lipid Peroxidation / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D010084:Oxidation-Reduction / Q000187:drug effects; D016716:PC12 Cells; D054464:Peroxiredoxins / Q000378:metabolism*; D010673:Pheochromocytoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D013778:Tetrazolium Salts / Q000378:metabolism; D013844:Thiazoles / Q000378:metabolism; D013879:Thioredoxins / Q000378:metabolism*; D014410:Tumor Stem Cell Assay
D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D013778:Tetrazolium Salts; D013844:Thiazoles; D013481:Superoxides; D013879:Thioredoxins; D054464:Peroxiredoxins; C499322:Parp1 protein, rat; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C022616:thiazolyl blue; D015655:1-Methyl-4-phenylpyridinium