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Rotenone-induced caspase 9/3-independent and -dependent cell death in undifferentiated and differentiated human neural stem cells.

Abstract
We used human neural stem cells (hNSCs) and their differentiated cultures as a model system to evaluate the mechanism(s) involved in rotenone (RO)- and camptothecin (CA)-induced cytotoxicity. Results from ultrastructural damage and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining indicated that RO-induced cytotoxicity resembled CA-induced apoptosis more than H(2)O(2)-induced necrosis. However, unlike CA-induced, caspase 9/3-dependent apoptosis, there was no increased activity in caspase 9, caspase 3 or poly (ADP-ribose) polymerase (PARP) cleavage in RO-induced cytotoxicity, in spite of time-dependent release of cytochrome c and apoptosis-inducing factor (AIF) following mitochondrial membrane depolarization and a significant increase in reactive oxygen species generation. Equal doses of RO and CA used in hNSCs induced caspase 9/3-dependent apoptosis in differentiated cultures. Time-dependent ATP depletion occurred earlier and to a greater extent in RO-treated hNSCs than in CA-treated hNSCs, or differentiated cultures treated with RO or CA. In conclusion, these results represent a unique ultrastructural and molecular characterization of RO- and CA-induced cytotoxicity in hNSCs and their differentiated cultures. Intracellular ATP levels may play an important role in determining whether neural progenitors or their differentiated cells follow a caspase 9/3-dependent or -independent pathway in response to acute insults from neuronal toxicants.
AuthorsJiang Li, Maria L Spletter, Delinda A Johnson, Lynda S Wright, Clive N Svendsen, Jeffrey A Johnson
JournalJournal of neurochemistry (J Neurochem) Vol. 92 Issue 3 Pg. 462-76 (Feb 2005) ISSN: 0022-3042 [Print] England
PMID15659217 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Enzyme Inhibitors
  • Reactive Oxygen Species
  • Topoisomerase I Inhibitors
  • Uncoupling Agents
  • Rotenone
  • Adenosine Triphosphate
  • CASP3 protein, human
  • CASP9 protein, human
  • Caspase 3
  • Caspase 9
  • Caspases
  • Camptothecin
Topics
  • Adenosine Triphosphate (metabolism)
  • Camptothecin (toxicity)
  • Caspase 3
  • Caspase 9
  • Caspases (metabolism)
  • Cell Death (drug effects)
  • Cell Differentiation
  • Cells, Cultured
  • DNA Fragmentation (drug effects)
  • Dose-Response Relationship, Drug
  • Enzyme Activation (drug effects)
  • Enzyme Inhibitors (toxicity)
  • Humans
  • In Situ Nick-End Labeling
  • Models, Biological
  • Neurons (cytology, drug effects, enzymology)
  • Reactive Oxygen Species (metabolism)
  • Rotenone (toxicity)
  • Stem Cells (cytology, drug effects, enzymology)
  • Topoisomerase I Inhibitors
  • Uncoupling Agents (toxicity)

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