Differential effect of calmodulin antagonists on MG132-induced mitochondrial dysfunction and cell death in PC12 cells
| Autor: | Hyoweon Bang, Young Su Han, Eun Sook Han, Chung Soo Lee |
|---|---|
| Rok vydání: | 2005 |
| Předmět: |
Programmed cell death
Mitochondrial Diseases Calmodulin Cell Survival Leupeptins Caspase 3 Cell Count macromolecular substances Trifluoperazine PC12 Cells chemistry.chemical_compound MG132 medicine Animals Drug Interactions Viability assay Enzyme Inhibitors Inner mitochondrial membrane Cell Size Sulfonamides biology Cell Death Dose-Response Relationship Drug General Neuroscience Imidazoles Cytochromes c Glutathione Cell biology Rats chemistry Caspases Proteasome inhibitor biology.protein Calcium Reactive Oxygen Species medicine.drug |
| Zdroj: | Brain research bulletin. 67(3) |
| ISSN: | 0361-9230 |
| Popis: | Defects in proteasome function have been suggested to be involved in the pathogenesis of neurodegenerative diseases. We examined the effect of calmodulin antagonists on proteasome inhibitor-induced mitochondrial dysfunction and cell viability loss in undifferentiated PC12 cells. Caspase inhibitors (z-IETD.fmk, z-LEHD.fmk and z-DQMD.fmk) and antioxidants attenuated cell death and decrease in GSH contents in PC12 cells treated with 20 microM MG132, a proteasome inhibitor. Calmodulin antagonists (trifluoperazine, W-7 and calmidazolium) had a differential inhibitory effect on the MG132-induced cell death and GSH depletion depending on concentration with a maximal inhibitory effect at 0.5-1 microM. Addition of trifluoperazine and W-7 reduced the MG132-induced nuclear damage, loss of the mitochondrial transmembrane potential followed by cytochrome c release, formation of reactive oxygen species and elevation of intracellular Ca(2+) levels in PC12 cells. Calmodulin antagonists at 5 microM exhibited a cytotoxic effect on PC12 cells but attenuated the cytotoxicity of MG132. The results suggest that the toxicity of MG132 on PC12 cells is mediated by activation of caspase-8, -9 and -3. Trifluoperazine and W-7 at the concentrations of 0.5-1 microM may attenuate the MG132-induced viability loss in PC12 cells by suppressing change in the mitochondrial membrane permeability and by lowering of the intracellular Ca(2+) levels as well as calmodulin inhibition. |
| Databáze: | OpenAIRE |
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