title: Manganese distribution across the blood-brain barrier. II. Manganese efflux from the brain does not appear to be carrier mediated.
abstract: There is concern about manganese (Mn) neurotoxicity. Mn can enter the brain by carrier-mediated influx. There have been no previous reports of investigation of Mn efflux from the brain. We used an established method that determines the rate of efflux out of the brain across the blood-brain barrier (BBB) from the product of the brain distribution volume (Vbrain) and the apparent elimination rate constant (Kel). Vbrain is determined as 54Mn uptake into rat parietal brain slices versus time. Kel is determined from the percentage of 54Mn remaining in the brain at various times after its discrete injection into the parietal cortex, compared to a reference compound which is expected to very slowly diffuse out of the brain. The Mn ion, Mn citrate and Mn transferrin (Mn Tf) were studied. 14C-sucrose and 14C-dextran were used as reference compounds. The volume of distribution of the Mn species in brain slices was approximately 3-5 ml/g, indicating concentrative uptake. Mn, as the Mn ion or Mn citrate, was injected into the brain with sucrose or dextran to determine Kel. Based on the rapid exchange rate of Mn with ligands and on thermodynamic calculations, injection of Mn ion or Mn citrate into the brain would be expected to result in rapid formation of the same Mn species, predominantly the Mn ion, Mn citrates and Mn phosphate, in brain extracellular fluid. After injection into the brain Mn did not efflux from the brain more rapidly than sucrose or dextran, which diffuse across the BBB. Brain capillary diffusion of the Mn ion and Mn citrate would be expected to be slower than sucrose or dextran. The rate of Mn efflux from the brain is consistent with diffusion.
authors.affiliation: College of Pharmacy, Graduate Center for Toxicology, University of Kentucky Medical Center, Lexington, KY, USA. ryokel@uky.edu
authors.forename: Robert A
authors.initials: RA
authors.lastname: Yokel
authors.forename: Janelle S
authors.initials: JS
authors.lastname: Crossgrove
authors.forename: Bonny L
authors.initials: BL
authors.lastname: Bukaveckas
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000502:physiology; D001812:Blood-Brain Barrier / Q000502:physiology*; D001921:Brain / Q000378:metabolism*; D019343:Citric Acid / Q000493:pharmacokinetics; D008345:Manganese / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014168:Transferrin / Q000493:pharmacokinetics
chemical_list: D014168:Transferrin; D019343:Citric Acid; D008345:Manganese