Document Detail


Simvastatin reduces the association of NMDA receptors to lipid rafts: a cholesterol-mediated effect in neuroprotection.
MedLine Citation:
PMID:  18323503     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND AND PURPOSE: Excess brain extracellular glutamate induced by cerebral ischemia leads to neuronal death, mainly through overactivation of N-methyl-D-aspartate (NMDA) receptors. The cholesterol-lowering drugs statins have been reported to protect from NMDA-induced neuronal death but, so far, the mechanism underlying this protection remains unclear. Because NMDA receptors have been reported to be associated with the cholesterol-rich membrane domains known as lipid rafts, we have investigated the effect of treatments that deplete cholesterol levels on excitotoxicity and on association of NMDA receptors to lipid rafts. METHODS: Primary neuronal cultures were pretreated with inhibitors of cholesterol synthesis and cholesterol, and NMDA-induced cell death was determined by measuring release of lactate dehydrogenase. Lipid raft fractions were isolated and Western blots were performed. RESULTS: Treatment with the inhibitors of cholesterol synthesis simvastatin, which inhibits the first step of cholesterol synthesis, or AY9944, which inhibits the last step of cholesterol synthesis, protected neurons from NMDA-induced neuronal death by 70% and 54%, respectively. Treatment with these compounds reduced neuronal cholesterol levels by 35% and 13%, respectively. Simvastatin and AY9944 reduced the association of the subunit 1 of NMDA receptors (NMDAR1) to lipid rafts by 42% and 21%, respectively, and did not change total expression of NMDAR1. Addition of cholesterol reduced neuroprotection by statins and AY9944, and partially reverted the effect of simvastatin on the association of NMDAR1 to lipid rafts. CONCLUSIONS: These data demonstrate that reduction of cholesterol levels protects from NMDA-induced neuronal damage probably by reducing the association of NMDA receptors to lipid rafts.
Authors:
Jovita Ponce; Natalia Pérez de la Ossa; Olivia Hurtado; Mónica Millan; Juan F Arenillas; Antonio Dávalos; Teresa Gasull
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-03-06
Journal Detail:
Title:  Stroke; a journal of cerebral circulation     Volume:  39     ISSN:  1524-4628     ISO Abbreviation:  Stroke     Publication Date:  2008 Apr 
Date Detail:
Created Date:  2008-03-25     Completed Date:  2008-04-23     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0235266     Medline TA:  Stroke     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1269-75     Citation Subset:  IM    
Affiliation:
Neuroscience Basic Research Lab, Fundació Institut d'Investigació en Ciències de Salut Germans Trias i Pujol, Badalona, Spain.
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MeSH Terms
Descriptor/Qualifier:
Animals
Anticholesteremic Agents / pharmacology*
Cell Death / drug effects
Cells, Cultured
Cerebral Cortex / cytology
Cholesterol / biosynthesis,  metabolism
Female
Membrane Microdomains / metabolism*
Neurons / cytology,  drug effects*,  metabolism
Neuroprotective Agents / pharmacology*
Neurotoxins / metabolism
Pregnancy
Rats
Receptors, N-Methyl-D-Aspartate / metabolism*
Simvastatin / pharmacology*
trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride / pharmacology
Chemical
Reg. No./Substance:
0/Anticholesteremic Agents; 0/Neuroprotective Agents; 0/Neurotoxins; 0/Receptors, N-Methyl-D-Aspartate; 366-93-8/trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride; 57-88-5/Cholesterol; 79902-63-9/Simvastatin

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


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