Regulation of taurine transport at the blood–brain barrier by tumor necrosis factor‐α, taurine and hypertonicity

Abstract

Taurine is the abundant sulfur-containing b-amino acid in brain where it exerts a neuroprotective effect. Although it is known that the blood-brain barrier (BBB) mediates taurine transport, the regulation of taurine transport have not been clarified yet. A conditionally immortalized rat brain capillary endothelial cells (TR-BBB13), an in vitro model of the BBB, exhibited [3 H]taurine uptake, which was dependent on both Na + and Cl -, and inhibited by b-alanine. Taurine transporter (TAUT) mRNA was detected in TR-BBB13 cells, and TAUT protein was also expressed at 70 kDa. TR-BBB13 cells exposed to 20 ng/mL TNF-a and under hypertonic conditions showed a 1.7-fold and 3.2-fold increase in [ 3 H]taurine uptake, respectively. In contrast, lipopolysaccharide and diethyl maleate did not significantly affect taurine uptake. The taurine uptake was reduced by pre-treatment with excess taurine (50 mM). The mRNA level of the TAUT in TNF-a and following hypertonic treatment was greater than that in control cells, whereas that under excess taurine conditions was lower than in controls. Therefore, taurine transport activity at the BBB appears to be regulated at the transcriptional level by cell damage, osmolality and taurine in the brain. Keywords: blood-brain barrier, immortalized brain capillary endothelial cell line, mRNA expression, osmoregulation, taurine transport, tumor necrosis factor-a. Taurine (2-aminoethanesulfonic acid) is one of the abundant free sulfur-containing b-amino acids in the CNS and is thought to play a role as an osmoregulator (Tuz et al. 2001) and a neuromodulator (Oja and Saransaari 1996). Taurine is also known to exert a neuroprotective effect against excitotoxic agents (French et al. 1986) and oxidative stress (Boldyrev et al. 1999). The taurine level in brain interstitial fluid is elevated in ischemia (Uchiyama-Tsuyuki et al. 1994;Matsumoto et al. 1996;Nakane et al. 1998), indicating that the brain controls its taurine level in response to cell damage for protecting neurons. The release of taurine from neuronal cells could be one of the regulating mechanisms. The release of taurine from hippocampal slices is increased under hypoglycemic and ischemic conditions, and in the presence of 2,4-dinitrophenol or media inducing free radical production by H 2 O 2 (Saransaari and Oja 2000). Another regulatory mechanism could involve the transport system at the blood-brain barrier (BBB). The BBB, which is formed by a complex of tight junctions of brain capillary endothelial cells, possesses a transport system for amino acids including taurine. The blood-to-brain influx Received July 16, 2002; revised manuscript received August 27, 2002; accepted September 11, 2002. Address correspondence and reprint requests to Professor Tetsuya Terasaki, Department of Molecular Biopharmacy and Genetics, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan. E-mail: terasaki@mail.pharm.tohoku.ac.jp Abbreviations used: BBB, blood-brain barrier; DEM, diethyl maleat...

The Inhibitory Effect of Rivastigmine and Galantamine on Choline Transport in Brain Capillary Endothelial Cells

“…Further, the BBB permeability clearances of several compounds estimated in TR-BBB cells appear quite similar to in vivo evaluations (Terasaki et al, 2003). TR-BBB cells have already been used to demonstrate that transporters such as taurine transporter (TauT), system A isoform (ATA2) are expressed in rat brain endothelium (Kang et al, 2002;Takanaga et al, 2002). Accordingly, we thought that TR-BBB cells are one of the best in vitro models of BBB, allowing for the investigation of the mechanism for transport of diverse compounds including various drugs.…”

The Change of Taurine Transport in Osteocytes by Oxidative Stress, Hypertonicity and Calcium Channel Blockers

“…Hyperosmotic culture medium (380 mOsm/kg) was prepared by adding 100 mM raffinose to normal culture medium. ]taurine uptake was performed through the previous report (Kang et al 2002) o C in the presence or absence of inhibitors. After appropriate time periods, uptake was terminated by removing the applied solution and cells were immersed in ice-cold ECF buffer.…”

“…Cytokine is one of the factors modulating taurine uptake. TNF-α, an inflammatory cytokine, increases expression of TauT mRNA and intracellular taurine uptake (Kang et al, 2002;Mochizuki et al, 2002). Pre-treatment TNF-α increases taurine uptake more in TR-BBB13 than in rat astrocyte and human intestinal Caco-2 cells (Chang et al, 2001).…”

Deletion of the γ-Aminobutyric Acid Transporter 2 (GAT2 and SLC6A13) Gene in Mice Leads to Changes in Liver and Brain Taurine Contents

“…Although TAUT plays a dominant role in taurine transport (30), there are many unresolved issues. For instance, at the blood-brain barrier, there is a taurine-sensitive GABA transport that is hard to attribute to TAUT alone because it is also sensitive to betaine and nipecotic acid (31)(32)(33)(34)(35)(36)(37). Deletion of the TAUT gene in mice resulted in dramatic reductions (Ͼ80%) in tissue taurine levels in several tissues, including brain, kidney, plasma, and retina, as well as skeletal and heart muscle (30), but immunocytochemistry for taurine suggested that the taurine loss in hepatocytes was only 30% (38).…”