Manganese (Mn), an essential elemental nutrient, is known to be neurotoxic at high occupational levels. We examined the transport of Mn across a monolayer of rat brain endothelial cell (RBE4) to evaluate whether an electromotive permeability mechanism is responsible for Mn transport across the blood-brain barrier (BBB). The (54)Mn(2+) apparent permeability and flux showed significant temperature-, energy- and pH-dependence, as well as partial sodium-dependence. Additionally, iron (Fe)-rich and Fe-deficient media significantly increased the apparent permeability of (54)Mn(2+). Finally, Mn flux and permeability decreased when RBE4 cells were grown in astrocyte-conditioned media (ACM), compared to standard alpha-media. These data reinforce observations that transport of Mn across the BBB occurs in part through active transport process.