Cholesterol synthesis inhibitors protect against platelet-activating factor-induced neuronal damage

Platelet-activating factor (PAF) is implicated in the neuronal damage that accompanies ischemia, prion disease and Alzheimer's disease (AD). Since some epidemiological studies demonstrate that statins, drugs that reduce cholesterol synthesis, have a beneficial effect on mild AD, we examined the...

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Bibliographic Details
Published in:	Journal of neuroinflammation Vol. 4; no. 1; p. 5
Main Authors:	Bate, Clive, Rumbold, Louis, Williams, Alun
Format:	Journal Article
Language:	English
Published:	England BioMed Central Ltd 2007 BioMed Central BMC
Subjects:	Animals Anticholesteremic agents Anticholesteremic Agents - pharmacology Cell Survival - drug effects Cell Survival - physiology Cells, Cultured Cholesterol - biosynthesis Dose-Response Relationship, Drug Humans Mice Neurons Neurons - drug effects Neurons - metabolism Neurons - pathology Platelet activating factor Platelet Activating Factor - antagonists & inhibitors Platelet Activating Factor - pharmacology Platelet Activating Factor - toxicity Short Report United Kingdom
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Summary:	Platelet-activating factor (PAF) is implicated in the neuronal damage that accompanies ischemia, prion disease and Alzheimer's disease (AD). Since some epidemiological studies demonstrate that statins, drugs that reduce cholesterol synthesis, have a beneficial effect on mild AD, we examined the effects of two cholesterol synthesis inhibitors on neuronal responses to PAF. Primary cortical neurons were treated with cholesterol synthesis inhibitors (simvastatin or squalestatin) prior to incubation with different neurotoxins. The effects of these drugs on neuronal cholesterol levels and neuronal survival were measured. Immunoblots were used to determine the effects of simvastatin or squalestatin on the distribution of the PAF receptor and an enzyme linked immunoassay was used to quantify the amounts of PAF receptor. PAF killed primary neurons in a dose-dependent manner. Pre-treatment with simvastatin or squalestatin reduced neuronal cholesterol and increased the survival of PAF-treated neurons. Neuronal survival was increased 50% by 100 nM simvastatin, or 20 nM squalestatin. The addition of mevalonate restored cholesterol levels, and reversed the protective effect of simvastatin. Simvastatin or squalestatin did not affect the amounts of the PAF receptor but did cause it to disperse from within lipid rafts. Treatment of neurons with cholesterol synthesis inhibitors including simvastatin and squalestatin protected neurons against PAF. Treatment caused a percentage of the PAF receptors to disperse from cholesterol-sensitive domains. These results raise the possibility that the effects of statins on neurodegenerative disease are, at least in part, due to desensitisation of neurons to PAF.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1742-2094 1742-2094
DOI:	10.1186/1742-2094-4-5