Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia.
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia.
J Pharm Sci. 2017 Sep;106(9):2625-2631. doi: 10.1016/j.xphs.2017.01.013. Epub 2017 Jan 16.
In addition to extruding drugs from the brain, P-glycoprotein (P-gp) at the blood-brain barrier (BBB) facilitates the brain-to-blood clearance of beta-amyloid (Aβ) and is down-regulated in Alzheimer's disease. Studies suggest that the mood-stabilizing drug lithium exerts a protective effect against Alzheimer's disease. Although the mechanisms underlying this effect are not fully understood, evidence suggests that lithium chloride (LiCl) increases P-gp expression in vitro, albeit at concentrations substantially outside the therapeutic window. Therefore, we investigated the effects of pharmacologically-relevant concentrations of LiCl on P-gp expression using in vitro and in vivo approaches. Swiss outbred mice administered LiCl (300 mg/kg/day, 21 days) showed no change in brain microvascular P-gp protein expression. Furthermore, P-gp transcript and protein levels were unaltered by LiCl (1.25-5 mM, 24 h) in human immortalized brain endothelial cells, while both gene and protein expression were significantly enhanced by the P-gp up-regulator, SR12813 by 1.5-fold and 2.0-fold, respectively. P-gp efflux function was also unaffected by LiCl in vitro, by measuring accumulation of the fluorescent P-gp substrate rhodamine-123. This suggests therefore that LiCl is unlikely to affect the BBB efflux of Aβ or other P-gp substrates at pharmacologically-relevant concentrations, suggesting that the Aβ-lowering effects of LiCl are unrelated to elevated BBB P-gp expression.
除了将药物从大脑中挤出外，血脑屏障（BBB）上的 P-糖蛋白（P-gp）还促进β-淀粉样蛋白（Aβ）从大脑向血液的清除，并且在阿尔茨海默病中下调。研究表明，心境稳定药物锂对阿尔茨海默病具有保护作用。尽管这种作用的机制尚未完全了解，但有证据表明，氯化锂（LiCl）在体外增加了 P-gp 的表达，尽管浓度大大超出了治疗窗口。因此，我们使用体外和体内方法研究了药理相关浓度的 LiCl 对 P-gp 表达的影响。给予锂（300mg/kg/天，21 天）的瑞士杂交小鼠的脑微血管 P-gp 蛋白表达没有变化。此外，LiCl（1.25-5mM，24 小时）对人永生化脑内皮细胞中的 P-gp 转录本和蛋白水平没有改变，而 P-gp 上调剂 SR12813 使基因和蛋白表达分别增强了 1.5 倍和 2.0 倍。LiCl 在体外也不会影响 P-gp 的外排功能，通过测量荧光 P-gp 底物罗丹明 123 的积累来测量。因此，这表明 LiCl 不太可能在药理相关浓度下影响 Aβ或其他 P-gp 底物的 BBB 外排，这表明 LiCl 降低 Aβ的作用与升高的 BBB P-gp 表达无关。
