Neurodegeneration Laboratory, Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI 02881, USA.
Curr Alzheimer Res. 2011 Dec;8(8):860-7. doi: 10.2174/156720511798192691.
Evidence from our laboratory suggests that tolfenamic acid has a potential for slowing the progression of Alzheimer's disease (AD) through lowering cortical levels of the β-amyloid precursor protein (APP) and its pathogenic amyloid beta (Aβ) intermediates [1]. In this study, we examined the ability of tolfenamic acid to cross the blood brain barrier (BBB) by predicting its logBB and logPS values, the indexes of BBB permeability, using computational models. We also determined, via in vitro methods, the brain penetration capacity factor [(K(IAM)/MW(4))x10(10)] using phosphatidylcholine column chromatography. The obtained logBB, logPS and (K(IAM)/MW(4))x10(10) values predicted that tolfenamic acid can passively transfer into the central nervous system (CNS). These results were validated in vivo using LC-MS analysis after administration of tolfenamic acid intravenously to guinea pigs and mice. The present study provides the first evidence of the ability of tolfenamic acid to cross the BBB and offers a comparative analysis of approaches used to predict the ability of compounds to penetrate into the brain.
我们实验室的证据表明，托芬那酸通过降低皮质层β-淀粉样前体蛋白（APP）及其致病淀粉样β（Aβ）中间产物的水平，具有减缓阿尔茨海默病（AD）进展的潜力[1]。在这项研究中，我们使用计算模型预测了托芬那酸的血脑屏障（BBB）穿透能力，预测其 logBB 和 logPS 值，这是 BBB 通透性的指标。我们还通过体外方法，使用磷脂酰胆碱柱层析法确定了脑穿透能力因子[(K(IAM)/MW(4))x10(10)]。得到的 logBB、logPS 和 (K(IAM)/MW(4))x10(10) 值预测托芬那酸可以被动地转移到中枢神经系统（CNS）。这些结果通过静脉注射托芬那酸后在豚鼠和小鼠体内进行 LC-MS 分析得到了验证。本研究首次提供了托芬那酸穿透 BBB 的能力的证据，并对用于预测化合物穿透大脑能力的方法进行了比较分析。
