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Research ArticleArticle

Differential Cell Death Induced by Salsolinol with and without Copper: Possible Role of Reactive Oxygen Species

Hyun-Jung Kim, Yunjo Soh, Jung-Hee Jang, Jeong-Sang Lee, Young J. Oh and Young-Joon Surh
Molecular Pharmacology September 2001, 60 (3) 440-449;
Hyun-Jung Kim
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Yunjo Soh
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Jung-Hee Jang
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Jeong-Sang Lee
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Young J. Oh
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Young-Joon Surh
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Abstract

Salsolinol (SAL), a novel dopaminergic catechol tetrahydroisoquinoline neurotoxin, has been speculated to contribute to the etiology of Parkinson's disease and neuropathology of chronic alcoholism. Our previous studies have demonstrated that SAL induces strand scission in øX174 supercoiled DNA and oxidative base modification in calf thymus DNA in the presence of cupric ion. We now report that treatment of rat pheochromocytoma (PC12) cells with SAL causes reduced viability, which was exacerbated by Cu2+. The copper chelator bathocuproinedisulfonic acid ameliorated cytotoxicity induced by SAL and Cu2+. N-Acetyl-l-cysteine and reduced glutathione protected against SAL- plus Cu2+-mediated PC12 cell death. Cells exposed to SAL underwent apoptosis, as revealed by characteristic morphological and biochemical changes. SAL treatment resulted in increased levels of Bax with a concomitant decrease in expression of Bcl-xL. Furthermore, SAL rapidly activated c-Jun N-terminal kinase, whereas the activity of extracellular signal-regulated protein kinase remained unchanged. Transfection with Bcl-xL or Bcl-2 led to protection against SAL-mediated PC12 cell death. Although SAL alone could cause apoptotic death in PC12 cells, cells treated with SAL together with Cu2+ became necrotic. Cells exposed to both SAL and Cu2+ exhibited higher levels of intracellular reactive oxygen species, malondialdehyde, and 8-oxo-7,8-dihydro-2′-deoxyguanosine than did those treated with SAL alone. These results suggest that copper accelerates redox cycling of SAL, leading to massive production of reactive oxygen species, which can divert the SAL-induced cell death to necrosis.

Footnotes

  • This work was supported by the Academic Research Fund (GE 997-019-D0008) awarded to Y.-J.S. from the Ministry of Education, Republic of Korea. This manuscript was prepared from a dissertation by H.-J.K. in partial fulfillment of the requirement for a Masters of Science at Seoul National University. Y.S. and J.-H.J. contributed equally to this work.

  • Abbreviations:
    SAL
    salsolinol
    ROS
    reactive oxygen species
    6-OHDA
    6-hydroxydopamine
    MAP
    mitogen-activated protein
    JNK
    c-Jun-N-terminal kinase
    ERK
    extracellular signal-mediated protein kinase
    BCS
    bathocuproinedisulfonic acid
    NAC
    N-acetyl-l-cysteine
    GSH
    reduced glutathione
    MTT
    3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
    DAPI
    4′,6-diamidino-2-phenylindole
    PBS
    phosphate-buffered saline
    TUNEL
    terminal deoxynucleotidyl transferase-mediated dUTP-X nick-end labeling
    DCF-DA
    2′,7′-dichlorodihydrofluorescein diacetate
    MDA
    malondialdehyde
    8-oxo-dGuo
    8-oxo-7,8-dihydro-2′-deoxyguanosine
    dGuo
    deoxyguanosine
    HPLC
    high-performance liquid chromatography
    • Received November 1, 2000.
    • Accepted May 11, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 60 (3)
Molecular Pharmacology
Vol. 60, Issue 3
1 Sep 2001
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Research ArticleArticle

Differential Cell Death Induced by Salsolinol with and without Copper: Possible Role of Reactive Oxygen Species

Hyun-Jung Kim, Yunjo Soh, Jung-Hee Jang, Jeong-Sang Lee, Young J. Oh and Young-Joon Surh
Molecular Pharmacology September 1, 2001, 60 (3) 440-449;

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Research ArticleArticle

Differential Cell Death Induced by Salsolinol with and without Copper: Possible Role of Reactive Oxygen Species

Hyun-Jung Kim, Yunjo Soh, Jung-Hee Jang, Jeong-Sang Lee, Young J. Oh and Young-Joon Surh
Molecular Pharmacology September 1, 2001, 60 (3) 440-449;
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