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 cells-derived BBB models (HBLEC) and human primary brain microvascular endothelial cells (hPBMEC) 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 significantly Li+ uptake in hCMEC/D3 by 52%, 51% and 47%, respectively, while S0859 (NBC inhibitor) increased 2.3-fold Li+ influx. 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 plasma membrane of brain endothelial cells.
Luo Hui Long conduit sa Thèse d'Université dans l'équipe 3.