Potential roles of NF-kappaB and ERK1/2 in cytoprotection against oxidative cell death induced by tetrahydropapaveroline.
Tetrahydropapaveroline (THP), a dopamine-derived tetrahydroisoquinoline catechol, has been suspected to be dopaminergic neurotoxin that elicits parkinsonism and neurobehavioral abnormalities associated with chronic alcoholism. THP has been detected in the brains of parkinsonian patients, and its urinary as well as brain level increases after l-3,4-dihydroxyphenylalanine treatment. Autoxidation or enzymatic oxidation of THP and subsequent generation of reactive oxygen species (ROS) may contribute to the degeneration of dopaminergic neurons induced by this tetrahydroisoquinoline alkaloid. In the present study, THP was found to elicit cytotoxicity in cultured rat pheochromocytoma (PC12) cells, which was completely blocked by reduced glutathione and N-acetyl-L-cysteine. THP-treated PC12 cells exhibited increased intracellular accumulation of ROS and underwent apoptosis as determined by poly(ADP-ribose)polymerase cleavage, an increased ratio of Bax to BclxL, terminal transferase-mediated dUTP nick end labeling, and nuclear fragmentation or condensation. THP treatment caused activation of the redox-sensitive transcription factor nuclear factor kappaB (NF-kappaB). Pretreatment of PC12 cells with NF-kappaB inhibitors, such as l-1-tosylamido-2-phenylethyl chloromethyl ketone and parthenolide, aggravated THP-induced cell death. THP treatment resulted in differential activation of mitogen-activated protein kinases as well as Akt/protein kinase B, thereby transmitting cell survival or death signals. In conclusion, THP induces apoptosis in PC12 cells by generating ROS. THP-mediated oxidative stress was accompanied by differential activation of intracellular signaling kinases and NF-kappaB.
Shin
Mi-Hyun
MH
Laboratory of Biochemistry and Molecular Toxicology, College of Pharmacy, Seoul National University, Seoul 151-742, South Korea.
Jang
Jung-Hee
JH
Surh
Young-Joon
YJ
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis; D002070:Butadienes / Q000494:pharmacology; D002374:Catalase / Q000494:pharmacology; D002470:Cell Survival; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism* / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*; D015394:Molecular Structure; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology*; D009570:Nitriles / Q000494:pharmacology; D018384:Oxidative Stress; D016716:PC12 Cells; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000032:analysis / Q000378:metabolism; D013765:Tetrahydropapaveroline / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
D000975:Antioxidants; C494828:Bax protein, rat; C494813:Bcl2l1 protein, rat; D002070:Butadienes; D016328:NF-kappa B; D009570:Nitriles; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; C113580:U 0126; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D013765:Tetrahydropapaveroline; D002374:Catalase; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases