Inserm U1144 , Paris F-75006 , France.
Université Paris Descartes UMR-S 1144 , Paris F-75006 , France.
Mol Pharm. 2018 Jul 2;15(7):2528-2538. doi: 10.1021/acs.molpharmaceut.8b00018. Epub 2018 Jun 14.
Variability in drug response to lithium (Li) is poorly understood and significant, as only 40% of patients with bipolar disorder highly respond to Li. Li can be transported by sodium (Na) transporters in kidney tubules or red blood cells, but its transport has not been investigated at the blood-brain barrier (BBB). Inhibition and/or transcriptomic strategies for Na transporters such as NHE (SLC9), NBC (SLC4), and NKCC (SLC12) were used to assess their role on Li transport in human brain endothelial cells. Na-free buffer was also used to examine Na/Li countertransport (NLCT) activity. The BBB permeability of Li evaluated in the rat was 2% that of diazepam, a high passive diffusion lipophilic compound. Gene expression of several Na transporters was determined in hCMEC/D3 cells, human hematopoietic stem-cell-derived BBB models (HBLEC), and human primary brain microvascular endothelial cells (hPBMECs) and showed the following rank order with close expression profile: NHE1 > NKCC1 > NHE5 > NBCn1, while NHE2-4, NBCn2, and NBCe1-2 were barely detected. Li influx in hCMEC/D3 cells was increased in Na-free buffer by 3.3-fold, while depletion of chloride or bicarbonate had no effect. DMA (NHE inhibitor), DIDS (anionic carriers inhibitor), and bumetanide (NKCC inhibitor) decreased Li uptake significantly in hCMEC/D3 by 52, 51, and 47%, respectively, while S0859 (NBC inhibitor) increased Li influx 2.3-fold. Zoniporide (NHE1 inhibitor) and siRNA against NHE1 had no effect on Li influx in hCMEC/D3 cells. Our study shows that NHE1 and/or NHE5, NBCn1, and NKCC1 may play a significant role in the transport of Li through the plasma membrane of brain endothelial cells.
锂（Li）反应的个体差异很大，目前了解甚少，但意义重大，因为仅有 40%的双相情感障碍患者对 Li 有高度反应。Li 可以通过肾小管或红细胞中的钠（Na）转运体进行转运，但在血脑屏障（BBB）中尚未对其转运进行研究。本研究使用抑制和/或 Na 转运体的转录组学策略，如 NHE（SLC9）、NBC（SLC4）和 NKCC（SLC12），来评估它们在人脑内皮细胞中对 Li 转运的作用。还使用无 Na 缓冲液来检查 Na/Li 反向转运（NLCT）活性。在大鼠中评估的 Li 通过 BBB 的能力是地西泮（一种高亲脂性被动扩散化合物）的 2%。在 hCMEC/D3 细胞、人造血干细胞衍生的 BBB 模型（HBLEC）和人原代脑微血管内皮细胞（hPBMEC）中确定了几种 Na 转运体的基因表达，其表达顺序如下：NHE1 > NKCC1 > NHE5 > NBCn1，而 NHE2-4、NBCn2 和 NBCe1-2 则几乎检测不到。在无 Na 缓冲液中，hCMEC/D3 细胞中的 Li 内流增加了 3.3 倍，而氯离子或碳酸氢根的耗竭则没有影响。DMA（NHE 抑制剂）、DIDS（阴离子载体抑制剂）和 bumetanide（NKCC 抑制剂）分别使 hCMEC/D3 中的 Li 摄取量显著减少 52%、51%和 47%，而 S0859（NBC 抑制剂）使 Li 内流增加 2.3 倍。Zoniporide（NHE1 抑制剂）和针对 NHE1 的 siRNA 对 hCMEC/D3 细胞中的 Li 内流没有影响。我们的研究表明，NHE1 和/或 NHE5、NBCn1 和 NKCC1 可能在 Li 通过脑内皮细胞膜的转运中发挥重要作用。
