S-Space Graduate School of Convergence Science and Technology (융합과학기술대학원) Dept. of Molecular and Biopharmaceutical Sciences (분자의학 및 바이오제약학과) Journal Papers (저널논문_분자의학 및 바이오제약학과)
Potential roles of NF-κB and ERK1/2 in cytoprotection against oxidative cell death induced by tetrahydropapaveroline
- Shin, Mi-Hyun; Jang, Jung-Hee; Surh, Young-Joon
- Issue Date
- Free Radical Biology and Medicine, Vol.36 No.9, pp.1185-1194
- L-3,4-dihydroxyphenylalanine; mitogen-activated protein kinases; nuclear factor kappa B; PC12 cells; redox cycling; tetrahydroisoquinoline; tetrahydropapaveroline; free radicals
- 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 Bcl(XL), 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. (C) 2004 Elsevier Inc. All rights reserved.
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