Manganese Distribution across the Blood-Brain Barrier. I. Evidence for Carrier-Mediated Influx of Managanese Citrate as well as Manganese and Manganese Transferrin

Manganese (Mn) is an essential element and a neurotoxicant. Regulation of Mn movement across the blood–brain barrier (BBB) contributes to whether the brain Mn concentration is functional or toxic. In plasma, Mn associates with water, small molecular weight ligands and proteins. Mn speciation may influence the kinetics of its movement through the BBB. In the present work, the brain influx rates of 54Mn2+, 54Mn citrate and 54Mn transferrin (54Mn Tf) were determined using the in situ brain perfusion technique. The influx rates were compared to their predicted diffusion rates, which were determined from their octanol/aqueous partitioning coefficients and molecular weights. The in situ brain perfusion fluid contained 54Mn2+, 54Mn citrate or 54Mn Tf and a vascular volume/extracellular space marker, 14C-sucrose, which did not appreciably cross the BBB during these short experiments (15–180 s). The influx transfer coefficient (Kin) was determined from four perfusion durations for each Mn species in nine brain regions and the lateral ventricular choroid plexus. The brain Kin was (5–13)×10−5, (3–51)×10−5, and (2–13)×10−5 ml/s/g for 54Mn2+, 54Mn citrate, and 54Mn Tf, respectively. Brain Kin values for any one of the three Mn species generally did not significantly differ among the nine brain regions and the choroid plexus. However, the brain Kin for Mn citrate was greater than Mn2+ and Mn Tf Kin values in a number of brain regions. When compared to calculated diffusion rates, brain Kin values suggest carrier-mediated brain influx of 54Mn2+, 54Mn citrate and 54Mn Tf. 55Mn citrate inhibited 54Mn citrate uptake, and 55Mn2+ inhibited 54Mn2+ uptake, supporting the conclusion of carrier-mediated brain Mn influx. The greater Kin values for Mn citrate than Mn2+ and its presence as a major non-protein-bound Mn species in blood plasma suggest Mn citrate may be a major Mn species entering the brain