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Manganese‐induced rat pheochromocytoma (PC12) cell death is independent of caspase activation
Author(s) -
Roth Jerome A.,
Feng Li,
Walowitz Jennifer,
Browne Richard W.
Publication year - 2000
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/1097-4547(20000715)61:2<162::aid-jnr7>3.0.co;2-g
Subject(s) - apoptosis , programmed cell death , lipid peroxidation , oxidative stress , cytotoxicity , chemistry , caspase , intracellular , mitochondrion , microbiology and biotechnology , cell damage , lipid peroxide , caspase 3 , biology , biochemistry , in vitro
Manganese (Mn) is an essential mineral that at high concentrations can produce an irreversible syndrome resembling Parkinson's disease. To examine the mechanism by which Mn elicits its toxic response, we have selected the rat pheochromocytoma cells (PC12) as our model system because it possesses much of the biochemical machinery associated with dopaminergic neurons. Mn‐induced PC12 cell death is both time and concentration dependent with approximately 50% cell survival at 48 hr in the presence of 0.3 mM Mn. To determine whether oxidative stress contributed to cytotoxicity induced by Mn, lipid peroxidation was assessed in Mn‐treated in PC12 cells. The highly sensitive HPLC assay that measures the lipid peroxide product, 9‐HODE, was used and results of these experiments demonstrate there was no increase in the lipid peroxidation in cells exposed to 0.3 mM Mn for 24 hr. Mn was found to stimulate the activation of the apoptotic marker proteins, p38 and caspase‐3 within the first 24 hr of treatment. The selective inhibitor of caspase‐3, DEVD‐CHO, and the nonselective caspase inhibitor, Z‐VAD‐FMK, however, fail to prevent Mn‐induced PC12 cell death. Studies were performed to determine the role of mitochondria in initiating or supporting Mn cytotoxicity, because Mn has been reported to cause changes in membrane permeability. Mn caused a decrease in ATP levels in PC12 cells in both a time and concentration dependent manner. We hypothesize that both apoptosis and necrosis contribute to PC12 cell death although the necrotic events prevail even when the apoptotic signaling is inhibited. J. Neurosci. Res. 61:162–171, 2000. © 2000 Wiley‐Liss, Inc.