Chronic administration of statins alters multiple gene expression patterns in mouse cerebral cortex.
Statins have been reported to lower the risk of developing Alzheimer's disease; however, the mechanism of this potentially important neuroprotective action is not understood. Lowering cholesterol levels does not appear to be the primary mechanism. Statins have pleiotropic effects in addition to lowering cholesterol, and statins may act on several different pathways involving distinct gene expression patterns that would be difficult to determine by focusing on a few genes or their products in a single study. In addition, gene expression patterns may be specific to a particular statin. To understand the molecular targets of statins in brain, DNA microarrays were used to identify gene expression patterns in the cerebral cortex of mice chronically treated with lovastatin, pravastatin, and simvastatin. Furthermore, brain statin levels were determined using liquid chromatography/tandem mass spectrometry. These studies revealed 15 genes involved in cell growth and signaling and trafficking that were similarly changed by all three statins. Overall, simvastatin had the greatest influence on expression as demonstrated by its ability to modify the expression of 23 genes in addition to those changed by all three drugs. Of particular interest was the expression of genes associated with apoptotic pathways that were altered by simvastatin. Reverse transcription-polymerase chain reaction experiments confirmed the microarray findings. All three drugs were detected in the cerebral cortex, and acute experiments revealed that statins are relatively rapidly removed from the brain. These results provide new insight into possible mechanisms for the potential efficacy of statins in reducing the risk of Alzheimer's disease and lay the foundation for future studies.
Johnson-Anuna
Leslie N
LN
Department of Pharmacology, University of Minnesota School of Medicine and Geriatric Research, VA Medical Center, One Veterans Drive, GRECC 11G, Minneapolis, MN 55417, USA.
Eckert
Gunter P
GP
Keller
Jan H
JH
Igbavboa
Urule
U
Franke
Cornelia
C
Fechner
Thomas
T
Schubert-Zsilavecz
Manfred
M
Karas
Michael
M
Müller
Walter E
WE
Wood
W Gibson
WG
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects / Q000235:genetics; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism; D002853:Chromatography, Liquid; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008148:Lovastatin / Q000494:pharmacology; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D009434:Neural Pathways / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D017035:Pravastatin / Q000494:pharmacology; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D019821:Simvastatin / Q000494:pharmacology
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D012313:RNA; D002784:Cholesterol; D008148:Lovastatin; D019821:Simvastatin; D017035:Pravastatin