Document Detail


Geranylgeranyl-pyrophosphate, an isoprenoid of mevalonate cascade, is a critical compound for rat primary cultured cortical neurons to protect the cell death induced by 3-hydroxy-3-methylglutaryl-CoA reductase inhibition.
MedLine Citation:
PMID:  10751437     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
We investigated the role of the intrinsic mevalonate cascade in the neuronal cell death (NCD) induced by the inhibition of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase in rat primary cortical neurons cultured from the brains of 17-d-old fetal SD rats. HMG-CoA reductase inhibitors induced NCD [HMG-CoA reductase inhibitor-induced NCD (H-NCD)] in time- and dose-dependent manners. The apoptotic characteristics were revealed by the formation of the DNA ladder and by the electron microscopical observation. During the progression of H-NCD, p53 was induced followed by the expression of Bax. Although the mevalonate completely inhibited H-NCD, the cholesterol did not. Thus, we examined two major metabolites of mevalonate, geranylgeranyl-pyrophosphate (GGPP) and farnesyl-pyrophosphate (FPP), using a novel liposome system for uptake into the cells. GGPP, not FPP, prohibited H-NCD with inhibition of the induction of p53 and Bax. The inhibition of HMG-CoA reductase decreased the amount of membrane-associated Rho small GTPase families, but not Ras small GTPase, and GGPP restored the blockage by HMG-CoA reductase inhibitor in the translocation or redistribution of Rho small GTPase families to membrane. These data indicated that (1) the inhibition of the intrinsic mevalonate cascade induces the apoptotic NCD with the induction of p53 followed by that of Bax, (2) the inhibition of HMG-CoA reductase concomitantly causes blockage of the translocation or redistribution of Rho small GTPase families, not Ras small GTPase, to membrane, and (3) GGPP, not FPP, is one of the essential metabolites in the mevalonate cascade for protecting neurons from H-NCD.
Authors:
T Tanaka; I Tatsuno; D Uchida; I Moroo; H Morio; S Nakamura; Y Noguchi; T Yasuda; M Kitagawa; Y Saito; A Hirai
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  The Journal of neuroscience : the official journal of the Society for Neuroscience     Volume:  20     ISSN:  1529-2401     ISO Abbreviation:  J. Neurosci.     Publication Date:  2000 Apr 
Date Detail:
Created Date:  2000-05-15     Completed Date:  2000-05-15     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  8102140     Medline TA:  J Neurosci     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  2852-9     Citation Subset:  IM    
Affiliation:
Second Department of Internal Medicine, Chiba University School of Medicine, Chiba, Japan.
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Count / drug effects
Cell Death / drug effects*,  physiology
Cells, Cultured
DNA Fragmentation
Female
Fetus
Hydroxymethylglutaryl CoA Reductases / drug effects*,  metabolism
Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
Mevalonic Acid / metabolism,  pharmacology*
Neurons / drug effects*,  physiology
Polyisoprenyl Phosphates / pharmacology*
Pregnancy
Prosencephalon
Proto-Oncogene Proteins c-bcl-2 / drug effects,  metabolism
Rats
Rats, Sprague-Dawley
Sesquiterpenes
Signal Transduction / drug effects,  physiology
Time Factors
Tumor Suppressor Protein p53 / drug effects,  metabolism
Chemical
Reg. No./Substance:
0/Hydroxymethylglutaryl-CoA Reductase Inhibitors; 0/Polyisoprenyl Phosphates; 0/Proto-Oncogene Proteins c-bcl-2; 0/Sesquiterpenes; 0/Tumor Suppressor Protein p53; 13058-04-3/farnesyl pyrophosphate; 150-97-0/Mevalonic Acid; 6699-20-3/geranylgeranyl pyrophosphate; EC 1.1.1.-/Hydroxymethylglutaryl CoA Reductases

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


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