HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 283, Issue 4, 1808-1817, January 25, 2008

This Article Full Text Full Text (PDF) All Versions of this Article: 283/4/1808    most recent M707442200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Clarke, R. M. Articles by Lynch, M. A. Search for Related Content PubMed PubMed Citation Articles by Clarke, R. M. Articles by Lynch, M. A. Social Bookmarking                      What's this?

A Pivotal Role for Interleukin-4 in Atorvastatin-associated Neuroprotection in Rat Brain^*

Rachael M. Clarke, Anthony Lyons¹, Florence O'Connell¹, Brian F. Deighan¹, Claire E. Barry, Ngozi G. Anyakoha, Anna Nicolaou, and Marina A. Lynch²

From the Trinity College Institute for Neuroscience, Physiology Department, Trinity College, Dublin 2, Ireland and the School of Pharmacy, University of Bradford, Bradford BD7 DP, United Kingdom

Inflammatory changes, characterized by an increase in pro-inflammatory cytokine production and up-regulation of the corresponding signaling pathways, have been described in the brains of aged rats and rats treated with the potent immune modulatory molecule lipopolysaccharide (LPS). These changes have been coupled with a deficit in long-term potentiation (LTP) in hippocampus. The evidence suggests that anti-inflammatory agents, which attenuate the LPS-induced and age-associated increase in hippocampal interleukin-1β (IL-1β) concentration, lead to restoration of LTP. Here we report that atorvastatin, a member of the family of agents that act as inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase, exerts powerful anti-inflammatory effects in brain and that these effects are mediated by IL-4 and independent of its cholesterol-lowering actions. Treatment of rats with atorvastatin increased IL-4 concentration in hippocampal tissue prepared from LPS-treated and aged rats and abrogated the age-related and LPS-induced increases in pro-inflammatory cytokines, interferon- (IFN) and IL-1β, and the accompanying deficit in LTP. The effect of atorvastatin on the LPS-induced increases in IFN and IL-1β was absent in tissue prepared from IL-4^–/– mice. The increase in IL-1β in LPS-treated and aged rats is associated with increased microglial activation, assessed by analysis of major histocompatibility complex II expression, and the evidence suggests that IFN may trigger this activation. We propose that the primary effect of atorvastatin is to increase IL-4, which antagonizes the effects of IFN, the associated increase in microglial activation, and the subsequent cascade of events.

Received for publication, September 5, 2007 , and in revised form, October 31, 2007.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These authors contributed equally to the work.

² To whom correspondence should be addressed. Tel.: 353-1-608-1770; Fax: 353-1-679-3545; E-mail: lynchma{at}tcd.ie.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?