Bateman Randall J, Siemers Eric R, Mawuenyega Kwasi G, Wen Guolin, Browning Karen R, Sigurdson Wendy C, Yarasheski Kevin E, Friedrich Stuart W, Demattos Ronald B, May Patrick C, Paul Steven M, Holtzman David M
Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
Ann Neurol. 2009 Jul;66(1):48-54. doi: 10.1002/ana.21623.
Accumulation of amyloid-beta (Abeta) by overproduction or underclearance in the central nervous system (CNS) is hypothesized to be a necessary event in the pathogenesis of Alzheimer's disease. However, previously, there has not been a method to determine drug effects on Abeta production or clearance in the human CNS. The objective of this study was to determine the effects of a gamma-secretase inhibitor on the production of Abeta in the human CNS.
We utilized a recently developed method of stable-isotope labeling combined with cerebrospinal fluid sampling to directly measure Abeta production during treatment of a gamma-secretase inhibitor, LY450139. We assessed whether this drug could decrease CNS Abeta production in healthy men (age range, 21-50 years) at single oral doses of 100, 140, or 280mg (n = 5 per group).
LY450139 significantly decreased the production of CNS Abeta in a dose-dependent fashion, with inhibition of Abeta generation of 47, 52, and 84% over a 12-hour period with doses of 100, 140, and 280mg, respectively. There was no difference in Abeta clearance.
Stable isotope labeling of CNS proteins can be utilized to assess the effects of drugs on the production and clearance rates of proteins targeted as potential disease-modifying treatments for Alzheimer's disease and other CNS disorders. Results from this approach can assist in making decisions about drug dosing and frequency in the design of larger and longer clinical trials for diseases such as Alzheimer's disease, and may accelerate effective drug validation. Ann Neurol 2009.
据推测，中枢神经系统（CNS）中淀粉样蛋白β（Aβ）因生成过多或清除不足而蓄积是阿尔茨海默病发病机制中的一个必要事件。然而，此前尚无方法可确定药物对人类CNS中Aβ生成或清除的影响。本研究的目的是确定γ-分泌酶抑制剂对人类CNS中Aβ生成的影响。
我们采用了一种最近开发的稳定同位素标记结合脑脊液采样的方法，以直接测量γ-分泌酶抑制剂LY450139治疗期间的Aβ生成。我们评估了该药物在100、140或280mg单剂量口服时（每组n = 5）能否降低健康男性（年龄范围21 - 50岁）的CNS Aβ生成。
LY450139以剂量依赖方式显著降低了CNS Aβ的生成，在12小时内，100、140和280mg剂量分别使Aβ生成抑制了47%、52%和84%。Aβ清除率无差异。
CNS蛋白质的稳定同位素标记可用于评估药物对作为阿尔茨海默病和其他CNS疾病潜在疾病修饰治疗靶点的蛋白质生成和清除率的影响。这种方法得到的结果有助于在设计针对阿尔茨海默病等疾病的更大规模、更长时间的临床试验时做出药物剂量和给药频率的决策，并可能加速有效的药物验证。《神经病学纪事》2009年
