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Thyroxine (T 4 ) enters the brain either directly across the blood–brain barrier (BBB) or indirectly  via  the choroid plexus (CP), which forms the blood–cerebrospinal fluid barrier (B-CSF-B). In this study, using isolated perfused CP of the sheep by single-circulation paired tracer and steady-state techniques, T4 transport mechanisms from blood into lateral ventricle CP has been characterized as the first step in the transfer across the B-CSF-B. After removal of sheep brain, the CPs were perfused with  125 I-T 4  and  14 C-mannitol. Unlabeled T 4  was applied during single tracer technique to assess the mode of maximum uptake ( U  max ) and the net uptake ( U  net ) on the blood side of the CP. On the other hand, in order to characterize T 4  protein transporters, steady-state extraction of  125 I-T 4  was measured in presence of different inhibitors such as probenecid, verapamil, BCH, or indomethacin. Increasing the concentration of unlabeled-T 4  resulted in a significant reduction in  U  max %, which was reflected by a complete inhibition of T 4  uptake into CP. In fact, the obtained  U  net % decreased as the concentration of unlabeled-T 4  increased. The addition of probenecid caused a significant inhibition of T 4  transport, in comparison to control, reflecting the presence of a carrier mediated process at the basolateral side of the CP and the involvement of multidrug resistance-associated proteins (MRPs: MRP1 and MRP4) and organic anion transporting polypeptides (Oatp1, Oatp2, and Oatp14). Moreover, verapamil, the P-glycoprotein (P-gp) substrate, resulted in ~34% decrease in the net extraction of T 4 , indicating that MDR1 contributes to T 4  entry into CSF. Finally, inhibition in the net extraction of T 4  caused by BCH or indomethacin suggests, respectively, a role for amino acid “L” system and MRP1/Oatp1 in mediating T 4  transfer. The presence of a carrier-mediated transport mechanism for cellular uptake on the basolateral membrane of the CP, mainly P-gp and Oatp2, would account for the efficient T 4  transport from blood to CSF. The current study highlights a carrier-mediated transport mechanism for T4 movement from blood to brain at the basolateral side of B-CSF-B/CP, as an alternative route to BBB.

frontiers in neurology

Thyroxine (T4) Transfer from Blood to Cerebrospinal Fluid in Sheep Isolated Perfused Choroid Plexus: Role of Multidrug Resistance-Associated Proteins and Organic Anion Transporting Polypeptides