Mok Simon Wing Fai, Thelen Karin M, Riemer Constanze, Bamme Theresa, Gültner Sandra, Lütjohann Dieter, Baier Michael
Project Neurodegenerative Diseases, Robert-Koch-Institute, Nordufer 20, 13353 Berlin, Germany.
Biochem Biophys Res Commun. 2006 Sep 22;348(2):697-702. doi: 10.1016/j.bbrc.2006.07.123. Epub 2006 Jul 31.
Prion diseases are fatal and at present there are neither cures nor palliative therapies known/available, which delay disease onset or progression. Cholesterol-lowering drugs have been reported to inhibit prion replication in infected cell cultures and to modulate inflammatory reactions. We aimed to determine whether simvastatin-treatment could delay disease onset in a murine prion model. Groups of mice were intracerebrally infected with two doses of scrapie strain 139A. Simvastatin-treatment commenced 100 days postinfection. The treatment did not affect deposition of misfolded prion protein PrP(res). However, expression of marker proteins for glia activation like major histocompatibility class II and galectin-3 was found to be affected. Analysis of brain cholesterol synthesis and metabolism revealed a mild reduction in cholesterol precursor levels, whereas levels of cholesterol and cholesterol metabolites were unchanged. Simvastatin-treatment significantly delayed disease progression and prolonged survival times in established prion infection of the CNS (p < or = 0.0003). The results suggest that modulation of glial responses and the therapeutic benefit observed in our murine prion model of simvastatin is not due to the cholesterol-lowering effect of this drug.
朊病毒疾病是致命的，目前既没有已知的治愈方法，也没有能够延缓疾病发作或进展的姑息疗法。据报道，降胆固醇药物可抑制感染细胞培养物中的朊病毒复制，并调节炎症反应。我们旨在确定辛伐他汀治疗是否能延缓小鼠朊病毒模型中的疾病发作。将几组小鼠脑内接种两剂羊瘙痒病毒株139A。辛伐他汀治疗在感染后100天开始。该治疗不影响错误折叠的朊病毒蛋白PrP（res）的沉积。然而，发现主要组织相容性复合体II类和半乳糖凝集素-3等胶质细胞激活标记蛋白的表达受到影响。对脑胆固醇合成和代谢的分析显示胆固醇前体水平略有降低，而胆固醇和胆固醇代谢物水平未变。在已建立的中枢神经系统朊病毒感染中，辛伐他汀治疗显著延缓了疾病进展并延长了存活时间（p≤0.0003）。结果表明，在我们的小鼠朊病毒模型中观察到的胶质细胞反应调节和辛伐他汀的治疗益处并非归因于该药物的降胆固醇作用。
