Lütjohann Dieter, Stroick Mark, Bertsch Thomas, Kühl Sandra, Lindenthal Bernhard, Thelen Karin, Andersson Ulla, Björkhem Ingemar, Bergmann Kv Klaus von, Fassbender Klaus
Department of Clinical Pharmacology, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany.
Steroids. 2004 Jun;69(6):431-8. doi: 10.1016/j.steroids.2004.03.012.
Recent epidemiological studies suggest that inhibitors of 3-hydroxy-3-methyl-glutaryl CoA reductase, so-called statins, are effective in lowering the prevalence of Alzheimer's disease. Whether the effect of statins is due to a local inhibition of cholesterol synthesis in the brain or whether it is mediated by the reduced levels of cholesterol in the circulation is not known. In the present work, we tested the possibility that high doses of lipophilic and hydrophilic statins, simvastatin and pravastatin, respectively, or a diet high in cholesterol could affect cholesterol homeostasis in the brain of guinea pigs. The total brain cholesterol levels were not affected by high-dose simvastatin or pravastatin treatment. Significantly lower levels of the cholesterol precursor lathosterol and its ratio to cholesterol were found in the brains of simvastatin and pravastatin-treated animals. 24S-Hydroxycholesterol, the transportable form of cholesterol across the blood-brain barrier, was significantly lower in the brain of pravastatin-treated animals. Excessive cholesterol feeding resulted in higher serum cholesterol levels but did not affect total brain cholesterol level. However, de novo cholesterol synthesis in the brain seemed to be down-regulated, as indicated by lower absolute levels and cholesterol-related ratios of lathosterol compared with controls. The passage of deuterium-labeled cholesterol across the blood-brain barrier in one animal was found to be approximately 1%. Our results suggest that brain cholesterol synthesis in guinea pigs can be slightly, but significantly, influenced by high doses of lipophilic and hydrophilic statins as well as by high dietary cholesterol intake, while total brain cholesterol content and thus, cholesterol homeostasis is maintained.
近期的流行病学研究表明，3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂，即所谓的他汀类药物，在降低阿尔茨海默病的患病率方面是有效的。他汀类药物的作用是由于对大脑中胆固醇合成的局部抑制，还是由循环中胆固醇水平的降低介导，目前尚不清楚。在本研究中，我们测试了分别给予高剂量的亲脂性他汀类药物辛伐他汀和亲水性他汀类药物普伐他汀，或高胆固醇饮食是否会影响豚鼠大脑中的胆固醇稳态。高剂量辛伐他汀或普伐他汀治疗并未影响大脑总胆固醇水平。在辛伐他汀和普伐他汀治疗的动物大脑中，发现胆固醇前体羊毛甾醇的水平及其与胆固醇的比率显著降低。普伐他汀治疗的动物大脑中，可穿过血脑屏障的胆固醇转运形式24S-羟基胆固醇显著降低。过量喂食胆固醇导致血清胆固醇水平升高，但并未影响大脑总胆固醇水平。然而，大脑中的从头胆固醇合成似乎被下调，这表现为与对照组相比，羊毛甾醇的绝对水平和与胆固醇相关的比率较低。在一只动物中，发现氘标记的胆固醇穿过血脑屏障的通过率约为1%。我们的结果表明，高剂量的亲脂性和亲水性他汀类药物以及高胆固醇饮食摄入可轻微但显著地影响豚鼠大脑中的胆固醇合成，同时维持大脑总胆固醇含量，进而维持胆固醇稳态。
