Delivery of Metals to Brain and the Role of the Blood-Brain Barrier

  • Quentin R. Smith
  • Olivier Rabin
  • Elsbeth G. Chikhale


Metals serve critical roles in brain as essential cofactors, catalysts, second messengers, and modulators of gene, enzyme, and receptor activity. Currently, eight metals, including calcium, magnesium, iron, copper, zinc, manganese, cobalt, and molybdenum, are known to be required for the normal development and function of the brian (Prohaska, 1987). Each must be supplied at specific levels to avoid signs of deficiency or toxic excess. Others, such as lead, aluminum, and mercury, are not essential, but are toxic if allowed to accumulate in the nervous system. Several metals, including iron, stimulate free radical formation and have been linked to oxidative damage in neurological disorders, including ischemia, stroke, and Parkinson’s disease (Riederer et al., 1989; Dexter et al., 1989; Griffiths and Crossman, 1993).


Iron Uptake Metal Uptake Transferrin Receptor Brain Uptake Neutral Amino Acid Transporter 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Abbott, N. J., 1992, Comparative physiology of the blood-brain barrier, in: Physiology and Pharmacology of the Blood-Brain Barrier, Handbook of Experimental Pharmacology, Volume 103, (M. W. B. Bradbury, ed.), Springer-Verlag, Berlin, pp. 371–396.CrossRefGoogle Scholar
  2. Aisen, P., Aasa, R., and Redfield, A. G., 1969, The chromium, manganese, and cobalt complexes of transferrin, J. Biol. Chem. 244:4628–4633.PubMedGoogle Scholar
  3. Aldred, A. R., Dickson, P. W., Marley, P. D., and Schreiber, G., 1987, Distribution of transferrin synthesis in brain and other tissues in the rat, J. Biol. Chem. 262:5293–5297.PubMedGoogle Scholar
  4. Allen, D. D., Orvig, C., and Yokel, R. A., 1995, Evidence for energy-dependent transport of aluminum out of brain extracellular fluid, Toxicology 98:31–39.PubMedCrossRefGoogle Scholar
  5. Aschner, M., and Aschner, J. L., 1990a, Mercury neurotoxicity: Mechanisms of blood-brain barrier transport, Neurosci. Biobehav. Rev. 14:169–176.PubMedCrossRefGoogle Scholar
  6. Aschner, M., and Aschner, J. L., 1990b, Manganese transport across the blood-brain barrier: Relationship to iron homeostasis, Brain Res. Bull. 24:857–860.PubMedCrossRefGoogle Scholar
  7. Aschner, M., and Gannon, M., 1994, Manganese (Mn) transport across the rat blood-brain barrier: Saturable and transferrin-dependent transport mechanisms, Brain Res. Bull. 33:345–349.PubMedCrossRefGoogle Scholar
  8. Banks, W. A., Kastin, A. J., Fasold, M. B., Barrera, C. M., and Augereau, G., 1988, Studies of the slow bidirectional transport of iron and transferrin across the blood-brain barrier, Brain Res. Bull. 21:881–885.PubMedCrossRefGoogle Scholar
  9. Bloch, B., Popovici, T., Chouham, S., Levin, M. J., Tuil, D., and Kahn, A., 1987, Transferrin gene expression in choroid plexus of the adult rat brain, Brain Res. Bull. 18:573–576.PubMedCrossRefGoogle Scholar
  10. Bradbury, M. W. B., 1979, The Concept of a Blood-Brain Barrier, Wiley & Sons, Chichester.Google Scholar
  11. Bradbury, M. W. B., 1992, Trace metal transport at the blood-brain barrier, in: Physiology and Pharmacology of the blood-brain barrier, Handbook of Experimental Pharmacology, Volume 103, (M. W. B. Bradbury, ed.), Springer-Verlag, Berlin, pp. 263–278.CrossRefGoogle Scholar
  12. Bradbury, M. W. B., 1994, Transport of Fe2+ into brain during cerebrovascular perfusion in the anaesthetized rat, J. Physiol. 479:37P.Google Scholar
  13. Bradbury, M. W. B., and Deane, R., 1986, Rate of uptake of lead-203 into brain and other soft tissues of the rat at constant radiotracer levels in plasma, Ann. NY Acad. Sci. 481:142–160.PubMedCrossRefGoogle Scholar
  14. Bradbury, M. W. B., and Deane, R., 1993, Permeability of the blood-brain barrier to lead, Neurotoxicology 14:131–136.PubMedGoogle Scholar
  15. Brightman, M. W., and Tao-Cheng, J. H., 1993, Tight junctions of brain endothelium and epithelium, in: The Blood-Brain Barrier (W M. Pardridge, ed.), Raven Press, New York.Google Scholar
  16. Buxani-Rice, S., Ueda, F., and Bradbury, M. W. B., 1994, Transport of zinc-65 at the blood-brain barrier during short cerebrovascular perfusion in the rat: Its enhancement by histidine, J. Neurochem. 62:665–672.PubMedCrossRefGoogle Scholar
  17. Citi, S., Sabanay, H., Jakes, R., Geiger, B., and Kendrick-Jones, J., 1988, Cingulin: a new peripheral component of tight junctions, Nature 333:272–276.PubMedCrossRefGoogle Scholar
  18. Crichton, R. R., ed., 1991, Inorganic Biochemistry of Iron Metabolism, Ellis Horwood, New York.Google Scholar
  19. Crone, C., 1984, Lack of selectivity to small ions in paracellular pathways in cerebral and muscle capillaries of the frog. J. Physiol (Lond) 353:317–337.Google Scholar
  20. Crone, C., and Olesen, S. P., 1982, Electrical resistance of brain microvascular endothelium, Brain Res. 241:49–55.PubMedCrossRefGoogle Scholar
  21. Davidsson, L., Lönnerdal, B., Sandström, B., Kunz, C., and Keen, C. L., 1989, Identification of transferrin as the major plasma carrier protein for manganese introduced orally or intravenously or after in vitro addition in the rat, J. Nutr. 119:1461–1464.PubMedGoogle Scholar
  22. Dawson, D. C., and Ballatori, N., 1995, Membrane transporters as sites of action and routes of entry for toxic metals, in: Toxicology of Metals: Biochemical Aspects, Handbook of Experimental Pharmacology, Volume 115, (R. A. Goyer and M. G. Cherian, eds.), Springer-Verlag, Berlin, pp. 53–76.Google Scholar
  23. Deane, R., and Bradbury, M. W. B., 1990, Transport of lead-203 at the blood-brain barrier during short cerebrovascular perfusion with saline in the rat, J. Neurochem. 54:905–914.PubMedCrossRefGoogle Scholar
  24. Dermietzel, R., and Krause, D., 1991, Molecular anatomy of the blood-brain barrier as defined by immunocytochemistry, Int. Rev. Cytol. 127:57–109.PubMedCrossRefGoogle Scholar
  25. Dexter, D. T., Wells, F. R., Lees, A. J., Agid, F., Agid, Y, Jenner, P., and Marsden, C. D., 1989, Increased nigral iron content and alterations in other metal ions occurring in brain in Parkinson’s disease, J. Neurochem. 52:1830–1836.PubMedCrossRefGoogle Scholar
  26. Fishman, J. B., Rubin, J. B., Handrahan, J. V, Connor, J. R., and Fine, R. E., 1987, Receptor-mediated transcytosis of transferrin across the blood-brain barrier, J. Neurosci. Res. 18:299–304.PubMedCrossRefGoogle Scholar
  27. Frame, M. D. S., and Milanick, 1991, Mn and Cd transport by the Na-Ca exchanger of ferret red blood cells, Am. J. Physiol. 261:C467-C475.Google Scholar
  28. Griffiths, P. D., and Crossman, A. R., 1993, Distribution of iron in the basal ganglia and neocortex in postmortem tissue in Parkinson’s disease and Alzheimer’s disease, Dementia 4:61–65.PubMedGoogle Scholar
  29. Huebers, H. A., and Finch, C. A., 1987, The physiology of transferrin and transferrin receptors, Physiol. Rev. 67:520–582.PubMedGoogle Scholar
  30. Idzerda, R. L., Huebers, H., Finch, C. A., and McKnight, G. S., 1986, Rat transferrin gene expression: Tissue-specific regulation by iron deficiency, Proc. Natl. Acad. Sci. USA 83:3723–3727.PubMedCrossRefGoogle Scholar
  31. Jefferies, W. A., Brandon, M. R., Hunt, S. V, Williams, A. F., Gatter, K. C., and Mason, D. Y, 1984, Transferrin receptor on endothelium of brain capillaries, Nature 312:162–163.PubMedCrossRefGoogle Scholar
  32. Kalaria, R. N., Sromek, S. M., Grahovac, I., and Harik, S. I., 1992, Transferrin receptors of rat and human brain and cerebral microvessels and their status in Alzheimer’s disease, Brain Res. 585:87–93.PubMedCrossRefGoogle Scholar
  33. Kasarskis, E. J., 1984, Zinc metabolism in normal and zinc-deficient rat brain, Exp. Neurology 85:114–127.CrossRefGoogle Scholar
  34. Kerper, L. E., Ballatori, N., and Clarkson, T. W., 1992, Methylmercury transport across the blood-brain barrier by an amino acid carrier, Am. J. Physiol. 262:R761-R765.Google Scholar
  35. Martin, R. B., Savory, J., Brown, S., Bertholf, R. L., and Wills, M. R., 1987, Transferrin binding of Al3+ and Fe3+, Clin. Chem. 33:405–407.PubMedGoogle Scholar
  36. May, P. M., Linder, P. W., and Williams, D. R., 1977, Computer simulation of metal-ion equilibria in biofluids: Models for the low-molecular-weight complex distribution of calcium (II), magnesium (II), manganese (II), iron (III), copper (II), and lead (II) ions in human blood plasma, J. Chem. Soc. Dalton 588–595.Google Scholar
  37. Morris, C. M., Candy, J. M., Court, J. A., Whitford, C. A., and Edwardson, J. A., 1987, The role of transferrin in the uptake of aluminium and manganese by the IMR 32 neuroblastoma cell line, Biochem Soc. Transactions 15:498–499.Google Scholar
  38. Morris, C. M., Keith, A. B., Edwardson, J. A., and Pullen, R. G. L., 1992, Uptake and distribution of iron and transferrin in the adult rat brain, J. Neurochem. 59:300–306.PubMedCrossRefGoogle Scholar
  39. Murphy, V. A., and Rapoport, S. I., 1992, Brain transfer coefficients for 67Ga: Comparison to 59Fe and effect of calcium deficiency, J. Neurochem. 58:898–902.PubMedCrossRefGoogle Scholar
  40. Murphy, V. A., Smith, Q. R., and Rapoport, S. I., 1986, Homeostasis of brain and cerebrospinal fluid calcium concentrations during chronic hypo- and hypercalcemia, J. Neurochem. 47:1735–1741.PubMedCrossRefGoogle Scholar
  41. Murphy, V. A., Smith, Q. R., and Rapoport, S. I., 1988a, Transfer coefficients for uptake of Ga-67, Cd-109, and Pb-203 into brain and cerebrospinal fluid (CSF), Abstr. Soc. Neurosci. 14:1037.Google Scholar
  42. Murphy, V. A., Smith, Q. R., and Rapoport, S. I., 1988b, Regulation of brain and cerebrospinal fluid calcium by brain barrier membranes following vitamin D-related chronic hypo- and hypercalcemia in rats, J. Neurochem. 51:1777–1782.PubMedCrossRefGoogle Scholar
  43. Murphy, V. A., Smith, Q. R., and Rapoport, S. I., 1989a, Rates of tracer cadmium uptake into various tissues, The Pharmacologist 31:137.Google Scholar
  44. Murphy, V. A., Smith, Q. R., and Rapoport, S. I., 1989b, Uptake and concentration of calcium in rat choroid plexus during chronic hypo- and hypercalcemia, Brain Res. 484:65–70.PubMedCrossRefGoogle Scholar
  45. Murphy, V. A., Wadhwani, K. C., Smith, Q. R., and Rapoport, S. I., 1991a, Saturable transport of manganese (II) across the rat blood-brain barrier, J. Neurochem. 57:948–954.PubMedCrossRefGoogle Scholar
  46. Murphy, V. A., Rosenberg, J. M., Smith, Q. R., and Rapoport, S. I., 1991b, Elevation of brain manganese in calcium-deficient rats, Neurotoxicology 12:255–264.PubMedGoogle Scholar
  47. Murphy, V. A., Smith, Q. R., and Rapoport, S. I., 1991c, Saturable transport of Ca into CSF in chronic hypo- and hypercalcemia, J. Neurosci. Res. 30:421–426.PubMedCrossRefGoogle Scholar
  48. Murphy, V. A., Embrey, E. C., Rosenberg, J. M., Smith, Q. R., and Rapoport, S. I., 1991d, Calcium deficiency enhances cadmium accumulation in the central nervous system, Brain Res. 557:280–284.PubMedCrossRefGoogle Scholar
  49. Narita, K., Kawasaki, F., and Kita, H., 1990, Mn and Mg influxes through Ca channels of motor nerve terminals are prevented by verapamil in frogs, Brain Res. 510:289–295.PubMedCrossRefGoogle Scholar
  50. Pardridge, W. M., Eisenberg, J., and Yang, J., 1987, Human blood-brain barrier transferrin receptor, Metabolism 36:892–895.PubMedCrossRefGoogle Scholar
  51. Petrov, T, Howarth, A. G., Krukoff, T. L., and Stevenson, B. R., 1994, Distribution of tight junction-associated protein ZO-1 in circumventricular organs of the CNS, Mol. Brain Res. 21:235–246.PubMedCrossRefGoogle Scholar
  52. Prohaska, J. R., 1987, Functions of trace elements in brain metabolism, Physiol. Rev. 67:858–901.PubMedGoogle Scholar
  53. Pullen, R. G. L., Candy, J. M., Morris, C. M., Taylor, G., Keith, A. B., and Edwardson, J. A., 1990, Gallium-67 as a potential marker for aluminium transport in rat brain: Implications for Alzheimer’s disease, J. Neurochem. 55:251–259.PubMedCrossRefGoogle Scholar
  54. Pullen, R. G. L., Franklin, P. A., and Hall, G. H., 1991, 65Zn uptake from blood into brain in the rat, J. Neurochem. 56:485–489.PubMedCrossRefGoogle Scholar
  55. Rabin, O., Hegedus, L., Bourre, J. M., and Smith, Q. R., 1993, Rapid brain uptake of manganese (II) across the blood-brain barrier, J. Neurochem. 61:509–517.PubMedCrossRefGoogle Scholar
  56. Radunovic, A., 1994, Transport of aluminium, compared with 67-Ga and 59-Fe, into brain and other tissues of the young adult rat, Ph.D. thesis, University of London.Google Scholar
  57. Rapoport, S. I., Ohno, K., and Pettigrew, K. D., 1979, Drug entry into the brain, Brain Res. 172:354–359.PubMedCrossRefGoogle Scholar
  58. Riederer, P., Sofie, E., Rausch, W. D., Schmidt, B., Reynolds, G. P., Jellinger, K., and Youdim, M. B. H., 1989, Transition metals, ferritin, glutathione, and ascorbic acid in Parkinsonian brains, J. Neurochem. 52:515–520.PubMedCrossRefGoogle Scholar
  59. Roberts, R., Sandra, A., Siek, G. C., Lucas, J. J., and Fine, R. E., 1992, Studies of the mechanism of iron transport across the blood-brain barrier, Ann. Neurol. 32:S43-S50.CrossRefGoogle Scholar
  60. Roberts, R. L., Fine, R. E., and Sandra, A., 1993, Receptor-mediated endocytosis of transferrin at the blood-brain barrier, J. Cell Sci. 104:521–532.PubMedGoogle Scholar
  61. Roskams, A. J., and Connor, J. R., 1990, Aluminum access to the brain: A role for transferrin and its receptor, Proc. Natl. Acad. Sci. USA 87:9024–9027.PubMedCrossRefGoogle Scholar
  62. Schielke, G. R, and Betz, A. L., 1992, Electrolyte transport, in: Physiology and Pharmacology of the Blood-Brain Barrier, Handbook of Experimental Pharmacology, Volume 103, (M. W. B. Bradbury, ed.), Springer-Verlag, Berlin pp. 221–243.CrossRefGoogle Scholar
  63. Schreiber, G., and Aldred, A. R., 1993, Molecular cloning of choroid plexus-specific transport proteins, in The Blood-Brain Barrier (W. M. Pardridge, ed.), Raven Press, New York, pp. 441–459.Google Scholar
  64. Skarlatos, S., Yoshikawa, T., and Pardridge, W. M., 1995, Transport of [125I]transferrin through the rat blood-brain barrier, Brain Res. 683:164–171.PubMedCrossRefGoogle Scholar
  65. Smith, Q. R., 1989, Quantitation of blood-brain barrier permeability, in: Implications of the Blood-Brain Barrier and Its Manipulation, Volume 1, (E. A. Neuwelt, ed.), Plenum Press, New York, pp. 85–118.CrossRefGoogle Scholar
  66. Smith, Q. R., 1990, Regulation of metal uptake and distribution within brain, in: Nutrition and the Brain, Volume 8 (R. J. Wurtman and J. J. Wurtman, eds.), Raven Press, New York, pp. 25–74.Google Scholar
  67. Smith, Q. R., 1993, Drug Delivery to brain and the role of carrier-mediated transport, in: Frontiers in Cerebral Vascular Biology: Transport and Its Regulation, (L. R. Drewes, and A. L. Betz, eds.), Plenum Press, New York, pp. 83–93.CrossRefGoogle Scholar
  68. Smith, Q. R., and Rapoport, S. I., 1986, Cerebrovascular permeability coefficients to sodium, potassium, and chloride, J. Neurochem. 46:1732–1742.PubMedCrossRefGoogle Scholar
  69. Suárez, N., and Eriksson, H., 1993, Receptor-mediated endocytosis of a manganese complex of transferrin into neuroblastoma (SHSY5Y) cells in culture, J. Neurochem. 61:127–131.PubMedCrossRefGoogle Scholar
  70. Tai, C., Smith, Q. R., and Rapoport, S. I., 1986, Calcium influxes into brain and cerebrospinal fluid are linearly related to plasma ionized calcium concentration, Brain Res. 385:227–236.PubMedCrossRefGoogle Scholar
  71. Takasato, Y, Rapoport, S. I., and Smith, Q. R., 1984, An in situ brain perfusion technique to study cerebrovascular transport in the rat, Am. J. Physiol. 247:H484-H493.Google Scholar
  72. Taylor, E. M., and Morgan, E. H., 1990, Developmental changes in transferrin and iron uptake by the brain in the rat, Dev. Brain Res. 55:35–42.CrossRefGoogle Scholar
  73. Taylor, E. M., and Morgan, E. H., 1991, Role of transferrin in iron uptake by the brain: a comparative study, J. Comp. Physiol. B 161:521–524.PubMedCrossRefGoogle Scholar
  74. Taylor, E. M., Crowe, A., and Morgan, E. H., 1991, Transferrin and iron uptake by the brain: Effects of altered iron status, J. Neurochem. 57:1584–1592.PubMedCrossRefGoogle Scholar
  75. Ueda, F., Raja, K. B., Simpson, R. J., Trowbridge, I. S., and Bradbury, M. W. B., 1993, Rate of 59Fe uptake into brain and cerebrospinal fluid and the influence thereon of antibodies against the transferrin receptor, J. Neurochem. 60:106–113.PubMedCrossRefGoogle Scholar
  76. Watson, P. M., Anderson, J. M., Vanltaille, C. M., and Doctorow, S. R., 1991, The tight junction-specific protein ZO-1 is a component of the human and rat blood-brain barriers, Neurosci. Lett. 129:6–10.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1997

Authors and Affiliations

  • Quentin R. Smith
    • 1
  • Olivier Rabin
    • 1
  • Elsbeth G. Chikhale
    • 1
  1. 1.Neurochemistry and Brain Transport Section, Laboratory of Neurosciences, National Institute on AgingNational Institutes of HealthBethesdaUSA

Personalised recommendations