Document Detail


Differential effect of calmodulin antagonists on MG132-induced mitochondrial dysfunction and cell death in PC12 cells.
MedLine Citation:
PMID:  16144659     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Chung Soo Lee; Eun Sook Han; Young Su Han; Hyoweon Bang
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Brain research bulletin     Volume:  67     ISSN:  0361-9230     ISO Abbreviation:  Brain Res. Bull.     Publication Date:  2005 Oct 
Date Detail:
Created Date:  2005-09-07     Completed Date:  2005-12-15     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  7605818     Medline TA:  Brain Res Bull     Country:  United States    
Other Details:
Languages:  eng     Pagination:  225-34     Citation Subset:  IM    
Affiliation:
Department of Pharmacology, College of Medicine, Chung-Ang University, Dong-jak Gu, Seoul 156-756, South Korea. leecs@cau.ac.kr
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MeSH Terms
Descriptor/Qualifier:
Animals
Calcium / metabolism
Calmodulin / agonists*
Caspase 3
Caspases / metabolism
Cell Count / methods
Cell Death / drug effects
Cell Size / drug effects
Cell Survival / drug effects
Cytochromes c / metabolism
Dose-Response Relationship, Drug
Drug Interactions
Enzyme Inhibitors / pharmacology*
Glutathione / metabolism
Imidazoles / pharmacology*
Leupeptins*
Mitochondrial Diseases / chemically induced,  prevention & control*
PC12 Cells
Rats
Reactive Oxygen Species / metabolism
Sulfonamides / pharmacology
Trifluoperazine / pharmacology
Chemical
Reg. No./Substance:
0/Calmodulin; 0/Enzyme Inhibitors; 0/Imidazoles; 0/Leupeptins; 0/Reactive Oxygen Species; 0/Sulfonamides; 117-89-5/Trifluoperazine; 133407-82-6/benzyloxycarbonylleucyl-leucyl-leucine aldehyde; 57265-65-3/calmidazolium; 65595-90-6/W 7; 70-18-8/Glutathione; 7440-70-2/Calcium; 9007-43-6/Cytochromes c; EC 3.4.22.-/Casp3 protein, rat; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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