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.
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Authors | Jiang Li, Maria L Spletter, Delinda A Johnson, Lynda S Wright, Clive N Svendsen, Jeffrey A Johnson |
Journal | Journal of neurochemistry
(J Neurochem)
Vol. 92
Issue 3
Pg. 462-76
(Feb 2005)
ISSN: 0022-3042 [Print] England |
PMID | 15659217
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)
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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
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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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