Impact of HMG-CoA reductase inhibition on brain pathology.
Over the past two decades, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (HMGCRIs), originally designed to lower cholesterol blood levels, have been found to affect GTPase signaling during normal intracellular tasks. This finding has prompted use of these drugs in pathological situations, where such signaling processes need to be manipulated. Here, we review recent progress on the outcome of modulating GTPase signaling after inhibition of protein prenylation by HMGCRIs. We also discuss current controversies over the direct implications of these cholesterol-lowering agents on cholesterol-rich membrane lipid rafts and associated signaling. By reviewing these two different cellular events and the evidence from clinical studies, an overall assessment can be made of the concept of interfering with the HMG-CoA reductase pathway in different brain pathologies. We thereby provide a rational link between the benefit of applying HMGCRIs in brain pathologies, such as multiple sclerosis, Alzheimer's disease and stroke, and the impact on signaling in specific cell types crucial to disease pathogenesis.
Zipp
Frauke
F
Cecilie-Vogt-Clinic for Molecular Neurology, Charité - Universitaetsmedizin Berlin, and Max-Delbrueck-Center for Molecular Medicine, 10117 Berlin, Germany. frauke.zipp@charite.de
Waiczies
Sonia
S
Aktas
Orhan
O
Neuhaus
Oliver
O
Hemmer
Bernhard
B
Schraven
Burkhard
B
Nitsch
Robert
R
Hartung
Hans-Peter
HP
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000503:physiopathology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000503:physiopathology; D015398:Signal Transduction; D020521:Stroke / Q000188:drug therapy* / Q000503:physiopathology
D000893:Anti-Inflammatory Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors