Sodium Transporters Are Involved in Lithium Influx in Brain Endothelial Cells

Abstract

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.

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Accumulation of Lithium in the Hippocampus of Patients With Bipolar Disorder: A Lithium-7 Magnetic Resonance Imaging Study at 7 Tesla

“…The heterogeneity of Li distribution corroborates similar results obtained at lower spatial resolutions (24,28). It supports the hypothesis of an active transport of Li inside the brain, possibly through sodium and magnesium transporters (12,13). In particular, the distribution of sodium channels across the central nervous system is complex, owing to the molecular diversity of each subtype of sodium transporter and the differential regulation of their expression.…”

“…It remains unclear, however, why Li would have localized effects on specific GM volumes. One hypothesis is that the distribution of Li throughout the brain could be heterogeneous owing to a discrepancy in the density of its available transporters, especially sodium channels (12,13). There is indeed strong evidence that these channels show distinct distribution across the different regions of the human brain (14)(15)(16)(17).…”

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“…The hPBMECs were cultured as previously described [31]. See Supporting Information for further details.…”