NSAIDs and enantiomers of flurbiprofen target γ-secretase and lower Aβ42 in vivo
NSAIDs and enantiomers of flurbiprofen target γ-secretase and lower Aβ42 in vivo
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DOI：
10.1172/jci200318162
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发表时间：
2003-08-01
影响因子：
15.9
通讯作者：
Golde, TE
中科院分区：
文献类型：
--
作者：
Eriksen, JL;Sagi, SA;Golde, TE
流行病学研究表明，长期使用NSAID与阿尔茨海默病（AD）发展风险降低相关。在这项研究中，分析了20种常用的NSAID、氨苯砜和氟比洛芬的对映体降低人H4细胞系中42-氨基酸形式的淀粉样β蛋白（A β 42）水平的能力。然后在淀粉样蛋白P蛋白前体（APP）转基因小鼠的急性给药研究中测试了13种NSAID和氟比洛芬的对映体，并评价了Abeta和药物的血浆和脑水平。这些研究表明（a）八种FDA批准的NSAID在体内降低A β 42，（B）NSAID降低细胞培养物中A β 42水平的能力高度预测其体内活性，（c）小鼠体内A β 42降低发生在人类可达到的药物水平，和（d）A β 42降低与布洛芬水平之间存在显著相关性。重要的是，氟比洛芬及其对映体选择性地降低A β 42水平在破碎的细胞γ-分泌酶测定，表明这些化合物直接靶向γ-分泌酶复合物，从APP产生A β。测试的化合物，甲氨酰胺酸，外消旋氟比洛芬，和纯化的R和S对映体的氟比洛芬降低A β 42水平的最大程度。由于R-氟比洛芬通过靶向γ-分泌酶降低A β 42水平，并且具有与抑制环氧合酶（考克斯）相关的降低的副作用，因此其是作为A β 42降低剂进行临床测试的极好候选物。
Epidemiologic studies demonstrate that long-term use of NSAIDs is associated with a reduced risk for the development of Alzheimer disease (AD). In this study, 20 commonly used NSAIDs, dapsone, and enantiomers of flurbiprofen were analyzed for their ability to lower the level of the 42-amino-acid form of amyloid beta protein (Abeta42) in a human H4 cell line. Thirteen of the NSAIDs and the enantiomers of flurbiprofen were then tested in acute dosing studies in amyloid P protein precursor (APP) transgenic mice, and plasma and brain levels of Abeta and the drug were evaluated. These studies show that (a) eight FDA-approved NSAIDs lower Abeta42 in vivo, (b) the ability of an NSAID to lower Abeta42 levels in cell culture is highly predicative of its in vivo activity, (c) in vivo Abeta42 lowering in mice occurs at drug levels achievable in humans, and (d) there is a significant correlation between Abeta42 lowering and levels of ibuprofen. Importantly, flurbiprofen and its enantiomers selectively lower Abeta42 levels in broken cell gamma-secretase assays, indicating that these compounds directly target the gamma-secretase complex that generates Abeta from APP. Of the compounds tested, meclofenamic acid, racemic flurbiprofen, and the purified R and S enantiomers of flurbiprofen lowered Abeta42 levels to the greatest extent. Because R-flurbiprofen reduces Abeta42 levels by targeting gamma-secretase and has reduced side effects related to inhibition of cyclooxygenase (COX), it is an excellent candidate for clinical testing as an Abeta42 lowering agent.