Potential roles of NF-kappaB and ERK1/2 in cytoprotection against oxidative cell death induced by tetrahydropapaveroline.

Abstract	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.
Authors	Mi-Hyun Shin, Jung-Hee Jang, Young-Joon Surh
Journal	Free radical biology & medicine (Free Radic Biol Med) Vol. 36 Issue 9 Pg. 1185-94 (May 01 2004) ISSN: 0891-5849 [Print] United States
PMID	15082072 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Antioxidants Bax protein, rat Bcl2l1 protein, rat Butadienes NF-kappa B Nitriles Proto-Oncogene Proteins Proto-Oncogene Proteins c-bcl-2 Reactive Oxygen Species U 0126 bcl-2-Associated X Protein bcl-X Protein Tetrahydropapaveroline Catalase Akt1 protein, rat Protein Serine-Threonine Kinases Proto-Oncogene Proteins c-akt Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 Mitogen-Activated Protein Kinases
Topics	Animals Antioxidants (pharmacology) Apoptosis Butadienes (pharmacology) Catalase (pharmacology) Cell Survival Mitogen-Activated Protein Kinase 1 (metabolism, physiology) Mitogen-Activated Protein Kinase 3 Mitogen-Activated Protein Kinases (metabolism, physiology) Molecular Structure NF-kappa B (metabolism, physiology) Nitriles (pharmacology) Oxidative Stress PC12 Cells Phosphorylation Protein Binding Protein Serine-Threonine Kinases (metabolism) Proto-Oncogene Proteins (metabolism) Proto-Oncogene Proteins c-akt Proto-Oncogene Proteins c-bcl-2 (metabolism) Rats Reactive Oxygen Species (analysis, metabolism) Tetrahydropapaveroline (pharmacology) bcl-2-Associated X Protein bcl-X Protein

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