NA-DEPENDENT AND PHLORHIZIN-INHIBITABLE TRANSPORT OF GLUCOSE AND CYCASIN IN BRAIN ENDOTHELIAL-CELLS()

Although cycasin (methylazoxymethanol beta-D-glucoside) is proposed to be a significant etiological factor for the prototypical neurodegener ative disorder Western Pacific amyotrophic lateral sclerosis and parki nsonism-dementia complex, the mechanism underlying transport of cycasi n across the blood-brain barrier (BBB) is unknown, We examined cycasin transport in cultured bovine brain endothelial cells, a major element of the BBB. Cycasin was taken up into endothelial cells in a dose-dep endent manner with maximal uptake observed at a concentration of 10 mu M. Cycasin uptake was significantly inhibited by alpha-methyl-D-gluco side, a specific analogue for the Na+-dependent glucose transporter (S GLT), by the SGLT inhibitor phlorizin, by replacement of extracellular NaCl with LiCl, and by dinitrophenol (DNP), an inhibitor of energy me tabolism. In addition, cycasin produced inward currents in a whole-cel l voltage clamp configuration, Peak currents were observed at IO mu M with a trend toward reduction at higher concentrations, and currents w ere clearly blocked by alpha-methyl-D-glucoside, phlorizin, and DNP. I n addition, cycasin never evoked currents in Na+-free extracellular so lution. These results suggest that cycasin is selectively transported across brain endothelial cells, possibly across the BBB by a Na+/energ y-dependent glucose transporter.