Cholesterol synthesis inhibitors protect against platelet-activating factor-induced neuronal damage
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BioMed Central
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Cholesterol synthesis inhibitors protect against platelet-activating factor-induced neuronal damage Clive Bate*, Louis Rumbold and Alun Williams Address: Department of Pathology and Infectious Diseases, Royal Veterinary College, Hawkshead Lane, North Mymms, Herts, AL9 7TA, UK Email: Clive Bate* - [email protected]; Louis Rumbold - [email protected]; Alun Williams - [email protected] * Corresponding author
Published: 18 January 2007 Journal of Neuroinflammation 2007, 4:5
doi:10.1186/1742-2094-4-5
Received: 27 September 2006 Accepted: 18 January 2007
This article is available from: http://www.jneuroinflammation.com/content/4/1/5 © 2007 Bate et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract Background: 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. Methods: 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. Results: 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. Conclusion: 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.
Background The hypothesis that brain cholesterol levels can affect the progression of Alzheimer's disease (AD) is now widely accepted [1]. One consequence of this hypothesis is the increasing interest in the use of statins as treatments for AD and other mild neurodegenerative disorders [2]. These
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