Differential cell death induced by salsolinol with and without copper: possible role of reactive oxygen species.
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 Cu(2+). The copper chelator bathocuproinedisulfonic acid ameliorated cytotoxicity induced by SAL and Cu(2+). N-Acetyl-L-cysteine and reduced glutathione protected against SAL- plus Cu(2+)-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-x(L). Furthermore, SAL rapidly activated c-Jun N-terminal kinase, whereas the activity of extracellular signal-regulated protein kinase remained unchanged. Transfection with Bcl-x(L) 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 Cu(2+) became necrotic. Cells exposed to both SAL and Cu(2+) 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.
Kim
H J
HJ
College of Pharmacy, Seoul National University, Seoul, Korea.
Soh
Y
Y
Jang
J H
JH
Lee
J S
JS
Oh
Y J
YJ
Surh
Y J
YJ
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D003300:Copper / Q000494:pharmacology*; D004347:Drug Interactions; D007546:Isoquinolines / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D016716:PC12 Cells; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*
D007546:Isoquinolines; D017382:Reactive Oxygen Species; D003300:Copper; C036617:salsolinol; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases