Document Detail

Inhibitors of interleukin-1 beta-converting enzyme-family proteases (caspases) prevent apoptosis without affecting decreased cellular ability to reduce 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide in cerebellar granule neurons.
MedLine Citation:
PMID:  9630648     Owner:  NLM     Status:  MEDLINE    
We assessed the possible role of interleukin-1beta-converting enzyme-family proteases (caspases) in apoptosis in cultured rat cerebellar granule neurons. CPP32 (caspase-3)-like protease activity was augmented by low KCl treatment, preceding neuronal cell death. Agents such as brain-derived neurotrophic factor (BDNF), dibutylyl cAMP, NMDA, actinomycin D, S-adenosyl-L-methionine, and spermine prevented apoptosis. For various neuroprotective agents, the degree of apoptosis prevention correlated with the prevention of the activation of CPP32-like protease. Furthermore, Z-Asp-2, 6-dichlorobenzoyloxy-methylketone (Z-Asp-CH2-DCB), Boc-Asp-fluoromethylketone (Boc-Asp-FMK), and Z-Val-Ala-Asp-fluoromethylketone (Z-VAD-FMK), which are inhibitors of caspases, also prevented apoptosis. In contrast to many other neuroprotective agents, these inhibitors of caspases showed little effect on the decrease of cellular 3-[4,5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide (MTT) reduction activity after low KCl treatment. The neurons rescued by these inhibitors of caspases during low KCl treatment were in a hypoenergic state in their ATP levels and vulnerable to subsequent treatment with medium containing high KCl or glutamate which induce an influx of Ca2+, but which are less toxic to normal neurons. These results suggest that caspase(s) are involved in the apoptosis of cerebellar granule neurons and that several agents protect neurons from death by blocking the activation of the protease(s). Although several caspase inhibitors examined in this study protect neurons from apoptosis, rescued neurons are vulnerable to subsequent stimuli that induce necrotic cell death.
J Harada; M Sugimoto
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Brain research     Volume:  793     ISSN:  0006-8993     ISO Abbreviation:  Brain Res.     Publication Date:  1998 May 
Date Detail:
Created Date:  1999-03-29     Completed Date:  1999-03-29     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0045503     Medline TA:  Brain Res     Country:  NETHERLANDS    
Other Details:
Languages:  eng     Pagination:  231-43     Citation Subset:  IM    
Copyright Information:
Copyright 1998 Elsevier Science B.V.
Neuroscience Research Laboratories, Sankyo, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
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MeSH Terms
Apoptosis / drug effects*
Calcium / metabolism,  physiology
Caspase 1 / antagonists & inhibitors*,  metabolism
Caspase 3
Caspases / metabolism
Cells, Cultured
Cerebellum / drug effects,  enzymology*
Coloring Agents / metabolism
Cysteine Proteinase Inhibitors / pharmacology*
Cytoplasmic Granules / drug effects,  enzymology*
Energy Metabolism / drug effects
Enzyme Activation / drug effects
Neurons / drug effects,  enzymology
Potassium Chloride / pharmacology
Rats, Sprague-Dawley
Tetrazolium Salts / metabolism*
Thiazoles / metabolism*
Reg. No./Substance:
0/Coloring Agents; 0/Cysteine Proteinase Inhibitors; 0/Tetrazolium Salts; 0/Thiazoles; 298-93-1/thiazolyl blue; 7440-70-2/Calcium; 7447-40-7/Potassium Chloride; EC 3.4.22.-/Casp3 protein, rat; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspases; EC 1

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