Manganese toxicokinetics at the blood-brain barrier

Increased manganese (Mn) use in manufacturing and in gasoline has raised concern about Mn-induced parkinsonism. Previous research indicated carrier-mediated brain entry but did not assess brain efflux. Using in situ rat brain perfusion, we studied influx across the blood-brain barrier (BBB*) of three predominant plasma Mn species available to enter the brain: Mn2+, Mn citrate, and Mn transferrin. Our results suggested transporter-mediated uptake of these species. The uptake rate was greatest for Mn citrate. Our results using the brain efflux index method suggested that diffusion mediates distribution from rat brain to blood. To characterize the carriers mediating brain Mn uptake, we used rat erythrocytes, an immortalized murine BBB cell line (b.End5), primary bovine brain endothelial cells (bBMECs), and Sprague Dawley and Belgrade rats. Studies with bBMECs and b.End5 cells suggested concentrative brain Mn2+ and Mn citrate uptake, respectively, consistent with carrier-mediated uptake. Mn2+ uptake positively correlated with pH, suggesting mediation by an electromotive force. Mn2+ uptake was not inhibited by iron or the absence of divalent metal transporter 1 (DMT-1) expression, suggesting an iron-transporter-independent mechanism. Mn2+ uptake inversely correlated with calcium and was affected by calcium channel modulators, suggesting a role for calcium channels. Rat erythrocyte results suggested monocarboxylate transporter 1 (MCT1) and anion exchange transporters do not mediate Mn citrate brain uptake. Considering carrier-mediated brain influx (but not efflux), repeated excessive Mn exposure should produce brain accumulation. Further work is necessary to identify the specific transporter or transporters mediating Mn distribution across the BBB.