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.

中文翻译：

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钠转运蛋白参与脑内皮细胞的锂内流

人们对锂（Li ⁺）药物反应的变异性了解甚少且意义重大，因为只有40％的躁郁症患者对Li ⁺高度反应。Li ⁺可以通过肾小管或红细胞中的钠（Na ⁺）转运蛋白转运，但尚未在血脑屏障（BBB）上研究其转运。Na ⁺转运蛋白（如NHE（SLC9），NBC（SLC4）和NKCC（SLC12））的抑制和/或转录组策略用于评估其在人脑内皮细胞中对Li ⁺转运的作用。还使用不含Na ^+的缓冲液来检查Na ⁺ / Li ⁺反转运（NLCT）活动。在大鼠中评估的Li ⁺的BBB渗透性是地西epa的2％，地西epa是一种高度被动扩散的亲脂性化合物。在hCMEC / D3细胞，人类造血干细胞衍生的BBB模型（HBLEC）和人类原代脑微血管内皮细胞（hPBMEC）中测定了几种Na ⁺转运蛋白的基因表达，并显示了以下具有紧密表达特征的等级顺序：NHE1 > NKCC1 > NHE5 > NBCn1，而几乎未检测到NHE2-4，NBCn2和NBCe1-2。Na ⁺中hCMEC / D3细胞的Li ^+内流增加不含缓冲液3.3倍，而氯化物或碳酸氢盐的消耗没有影响。DMA（NHE抑制剂），DIDS（阴离子载体抑制剂）和布美他尼（NKCC抑制剂）分别显着降低hCMEC / D3中的Li ⁺吸收，分别降低52％，51％和47％，而S0859（NBC抑制剂）增加Li ⁺流入2.3 -折叠。Zoniporide（NHE1抑制剂）和针对NHE1的siRNA对hCMEC / D3细胞的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 ⁺通过脑内皮细胞质膜的运输中起重要作用。