Sodium Transporters Are Involved in Lithium Influx in Brain Endothelial Cells

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.