Zipp Frauke, Waiczies Sonia, Aktas Orhan, Neuhaus Oliver, Hemmer Bernhard, Schraven Burkhard, Nitsch Robert, Hartung Hans-Peter
Cecilie-Vogt-Clinic for Molecular Neurology, Charité - Universitaetsmedizin Berlin, and Max-Delbrueck-Center for Molecular Medicine, 10117 Berlin, Germany.
Trends Pharmacol Sci. 2007 Jul;28(7):342-9. doi: 10.1016/j.tips.2007.05.001. Epub 2007 Jun 15.
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.
在过去二十年中，最初设计用于降低血液胆固醇水平的3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂（HMGCRIs），已被发现会在正常细胞内活动过程中影响GTP酶信号传导。这一发现促使这些药物被用于需要操控此类信号传导过程的病理情况。在此，我们回顾了HMGCRIs抑制蛋白质异戊二烯化后调节GTP酶信号传导结果的最新进展。我们还讨论了目前关于这些降胆固醇药物对富含胆固醇的膜脂筏及相关信号传导的直接影响的争议。通过回顾这两种不同的细胞事件以及临床研究证据，可以对在不同脑部病变中干扰HMG-CoA还原酶途径的概念进行全面评估。从而，我们在将HMGCRIs应用于脑部病变（如多发性硬化症、阿尔茨海默病和中风）的益处与对疾病发病机制至关重要的特定细胞类型中的信号传导影响之间建立了合理联系。
