, Volume 20, Supplement 1, pp 246–254 | Cite as

Transport of nutrients and hormones through the blood-brain barrier

  • W. M. Pardridge


An understanding of the mechanisms of transport of circulating nutrients and hormones through the brain capillary wall, i. e., the blood-brain barrier, is important because the availability in brain of these substances influences a number of cerebral metabolic pathways. For example, the utilization by brain of glucose, ketone bodies and branched chain amino acids or the production of monoamines, acetylcholine, carnosine, and nucleosides may under certain conditions be influenced by BBB transport of circulating precursor nutrients. Steroid and thyroid hormones readily traverse the BBB via lipid-mediation and carrier-mediation, respectively. Although the steroid and thyroid hormones are tightly bound by plasma proteins, protein-bound hormone, not the free (dialyzable) moiety, is the major plasma fraction transported through the BBB. With regard to circulating peptides, the available evidence indicates peptides rapidly distribute into brain interstitial space of the circumventricular organs of brain, i. e., about six small regions around the ventricles which lack a BBB. Conversely, the absence of peptide carriers in the BBB prevents the rapid distribution of peptides into the vast majority of brain interstitial or synaptic spaces. However, recent studies indicate that some peptides, e. g., insulin, may bind specific receptors on the blood side of the BBB and thereby transmit messages to cells on the brain side of the BBB, without the peptide traversing the capillary wall.

Key words

Blood-brain barrier brain metabolism steroid hormones thyroid hormones peptides 


  1. 1.
    Brightman MW (1975) Morphology of blood-brain interfaces. In: Bito LZ, Davson H, Fenstermacher JD (eds) The ocular and cerebrospinal fluids, p1-25. NIH, Bethesda MarylandGoogle Scholar
  2. 2.
    Pardridge WM, Mietus LJ (1979) Transport of steroid hormones through the rat blood-brain barrier. J Clin Invest 64: 145–154CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Pardridge WM, Mietus LJ (1980) Transport of albumin-bound melatonin through the blood-brain barrier. J Neurochem 34: 1761–1763CrossRefPubMedGoogle Scholar
  4. 4.
    Pardridge WM, Mietus LJ (1980) Palmitate and cholesterol transport through the blood-brain barrier. J Neurochem 34: 463–466CrossRefPubMedGoogle Scholar
  5. 5.
    Pardridge WM, Oldendorf WH (1977) Transport of metabolic substrates through the blood-brain barrier. J Neurochem 28: 5–12CrossRefPubMedGoogle Scholar
  6. 6.
    Cornford EM, Braun LD, Oldendorf WH (1978) Carrier mediated blood-brain barrier transport of choline and certain choline analogs. J Neurochem 30: 299–308CrossRefPubMedGoogle Scholar
  7. 7.
    Pardridge WM (1979) Regulation of amino acid availability to brain: Selective control mechanisms for glutamate. In: Filer Jr LF, et al (eds) Advances in biochemistry and physiology, Raven Press, New York, p 125–137Google Scholar
  8. 8.
    Pardridge WM (1979) Carrier-mediated transport of thyroid hormones through the rat blood-brain barrier: Primary role of albumin-bound hormone. Endocrinology 105: 605–612CrossRefPubMedGoogle Scholar
  9. 9.
    Wurtman RJ, Fernstrom JD (1975) Control of brain monoamine synthesis by diet and plasma amino acids. Am J Clin Nutr 28: 638–647PubMedGoogle Scholar
  10. 10.
    Pardridge WM, Cornford EM, Braun LD, Oldendorf WH (1979) Transport of choline and choline analogues through the blood-brain barrier. In: Barbeau A, Growdon JH, Wurtman RJ (eds) Nutrition and brain, vol. 5, Raven Press, New York, pp 25–33Google Scholar
  11. 11.
    Pardridge WM (1979) The role of blood-brain barrier transport of tryptophan and other neutral amino acids in the regulation of substrate-limited pathways of brain metabolism. In: Baumann P (ed) Transport mechanisms of tryptophan in blood cells, nerve cells, and at the blood-brain barrier, p 43–54. Springer, Berlin Heidelberg New YorkCrossRefGoogle Scholar
  12. 12.
    Owen OE, Markus H, Barshik S, Mozzoli M (1973) Relationship between plasma and muscle concentrations of ketone bodies and free fatty acids in fed, starved and alloxan-diabetic states. Biochem J 134: 499–506CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Hawkins RA, Biebuyck JP (1979) Ketone bodies are selectively used by individual brain regions. Science 205: 325–327CrossRefPubMedGoogle Scholar
  14. 14.
    Gjedde A, Crone C (1975) Induction processes in blood-brain transfer of ketone bodies during starvation. Am J Physiol 229: 1165–1169PubMedGoogle Scholar
  15. 15.
    Moore TJ, Lione AP, Sugden MC, Regen DM (1976) β-Hydroxybutyrate transport in rat brain: developmental and dietary modulations. Am J Physiol 230: 619–630PubMedGoogle Scholar
  16. 16.
    Kipnis DM, Helmreich E, Cori CF (1959) Studies of tissue permeability. IV. The distribution of glucose between plasma and muscle. J Biol Chem 234: 165–170PubMedGoogle Scholar
  17. 17.
    Lewis LD, Ljunggren B, Norberg K, Siesjo BK (1974) Changes in carbohydrate substrates, amino acids and ammonia in the brain during insulin-induced hypoglycemia. J Neurochem 23: 659–671CrossRefPubMedGoogle Scholar
  18. 18.
    Betz AL, Gilboe DD, Drewes LR (1974) Effects of anoxia on net uptake and unidirectional transport of glucose into the isolated dog brain. Brain Res 67: 307–316CrossRefPubMedGoogle Scholar
  19. 19.
    Chapman AG, Meldrum BS, Siesjo BK (1977) Cerebral metabolic changes during prolonged epileptic seizures in rats. J Neurochem 28: 1025–1035CrossRefPubMedGoogle Scholar
  20. 20.
    Thurston JH, Pollock PG, Warren SK, Jones EM (1970) Reduced brain glucose with normal plasma glucose in salicylate poisoning. J Clin Invest 49: 2139–2145CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Phelps ME, Huang SC, Hoffman EJ, Selin C, Sokoloff L, Kuhl DE (1979) Tomographic measurement of local cerebral glucose metabolic rate in humans with (F-18) 2-fluoro-2-deoxy-D-glucose: Validation of method. Ann Neurol 6: 371–388CrossRefPubMedGoogle Scholar
  22. 22.
    Fernstrom JD, Wurtman RJ (1971) Brain serotonin content: physiological dependence on plasma tryptophan levels. Science 173: 149–151CrossRefPubMedGoogle Scholar
  23. 23.
    Gibson CJ, Wurtman RJ (1978) Physiological control of brain norepinephrine synthesis by brain tyrosine concentration. Life Sci 22: 1399–1406CrossRefPubMedGoogle Scholar
  24. 24.
    Taylor KM, Snyder SH (1972) Dynamics of the regulation of histamine levels in mouse brain. J Neurochem 19: 341–354CrossRefPubMedGoogle Scholar
  25. 25.
    Rubin RA, Ordonez LA, Wurtman RJ (1974) Physiological dependence of brain methionine and S-adenosylmethionine concentrations on serum amino acid pattern. J Neurochem 23: 227–231CrossRefPubMedGoogle Scholar
  26. 26.
    Chaplin ER, Goldberg AL, Diamond I (1976) Leucine oxidation in brain slices and nerve endings. J Neurochem 26: 701–707CrossRefPubMedGoogle Scholar
  27. 27.
    Cohen EL, Wurtman RJ (1976) Brain acetylcholine: Control by dietary choline. Science 191: 561–562CrossRefPubMedGoogle Scholar
  28. 28.
    Ames III A, Parks JM (1976) Functional homogeneity of leucine pool in retina cells. J Neurochem 27: 1017–1025CrossRefPubMedGoogle Scholar
  29. 29.
    Marz R, Wohlhueter RM, Plagemann PGW (1979) Purine and pyrimidine transport and phosphoribosylation and their interaction in overall uptake by cultured mammalian cells. A re-evaluation. J Biol Chem 254: 2329–2338PubMedGoogle Scholar
  30. 30.
    Nordstrom CH, Rehncrona S, Siesjo BK, Westerberg E (1977) Adenosine in rat cerebral cortex: Its determination, normal values, and correlation to AMP and cyclic AMP during shortlasting ischemia. Acta Physiol Scand 101: 63–71CrossRefPubMedGoogle Scholar
  31. 31.
    Pritchard JB, O'Connor N, Oliver JM, Berlin RD (1975) Uptake and supply of purine compounds by the liver. Am J Physiol 229: 967–972PubMedGoogle Scholar
  32. 32.
    Braun LD, Cornford EM, Oldendorf WH (1980) Newborn rabbit blood-brain barrier is selectively permeable and differs substantially from the adult. J Neurochem 34: 147–152CrossRefPubMedGoogle Scholar
  33. 33.
    Møllgard K, Saunders NR (1975) Complex tight junctions of epithelial and of endothelial cells in early foetal brain. J Neurocytol 4: 453–568CrossRefGoogle Scholar
  34. 34.
    James JH, Escourrou J, Fischer JE (1978) Blood-brain neutral amino acid transport activity is increased after portacaval anastomosis. Science 200: 1395–1397CrossRefPubMedGoogle Scholar
  35. 35.
    James JH, Jeppsson B, Ziparo V, Fischer JE (1979) Hyperammonaemia, plasma aminoacid imbalance, and blood-brain aminoacid transport: a unified theory of portal-systemic encephalopathy. Lancet II: 772–775CrossRefGoogle Scholar
  36. 36.
    Oldendorf WH (1971) Brain uptake of radiolabeled amino acids, amines, and hexoses after arterial injection. Am J Physiol 221: 1629–1639PubMedGoogle Scholar
  37. 37.
    Perry TL, Hansen S, Kennedy J (1975) CSF amino acids and plasma — CSF amino acid ratios in adults. J Neurochem 24: 587–589CrossRefPubMedGoogle Scholar
  38. 38.
    Toth J Lajtha A (1977) Rates of exchange of free amino acids between plasma and brain in mice. Neurochem Res 2: 149–160CrossRefPubMedGoogle Scholar
  39. 39.
    Betz AL, Gilboe DD, Drewes LR (1975) Accelerative exchange diffusion kinetics of glucose between blood and brain and its relation to transport during anoxia. Biochim Biophys Acta 401: 416–428CrossRefPubMedGoogle Scholar
  40. 40.
    Gold EM (1979) The Cushing syndromes: Changing views of diagnosis and treatment. Ann Intern Med 90: 829–844CrossRefPubMedGoogle Scholar
  41. 41.
    Sanders V (1962) Neurologic manifestations of myxedema. N Engl J Med 266: 547–552CrossRefGoogle Scholar
  42. 42.
    Gorski RA (1973) Perinatal effects of sex steroids on brain development and function. Prog Brain Res 39: 149–163CrossRefPubMedGoogle Scholar
  43. 43.
    Pardridge WM, Mietus LJ (1980) Influx of thyroid hormones into rat liver in vivo. Primary role of protein-bound hormone. J Clin Invest 66: 367–374CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Pardridge WM, Mietus LJ (1979) Transport of protein-bound steroid hormones into liver in vivo. Am J Physiol 237: E367-E372PubMedGoogle Scholar
  45. 45.
    Pardridge WM, Mietus LJ (1980) Effects of progesteronebinding globulin versus a progesterone antiserum on steroid hormone transport through the blood-brain barrier. Endocrinology 106: 1137–1141CrossRefPubMedGoogle Scholar
  46. 46.
    Cornford EM, Braun LD, Crane PD, Oldendorf WH (1978) Blood-brain barrier restriction of peptides and the low uptake of enkephalins. Endocrinology 103: 1297–1303CrossRefPubMedGoogle Scholar
  47. 47.
    Rapoport SI, Klee WA, Pettigrew KD, Ohno K (1980) Entry of opioid peptides into the central nervous system. Science 207: 84–86CrossRefPubMedGoogle Scholar
  48. 48.
    Pardridge WM, Frank HJL, Cornford EM, Braun LD, Crane PD, Oldendorf WH (1981) Neuropeptides and the blood-brain barrier. In: Martin JB, et al. (eds) Neurosecretion and brain peptides. Raven Press, New York, p 321–328Google Scholar
  49. 49.
    Goodner CJ, Berrie MA (1977) The failure of rat hypothalamic tissues to take up labeled insulin in vivo or to respond to insulin in vitro. Endocrinology 101: 605–612CrossRefPubMedGoogle Scholar
  50. 50.
    Woods SC, Porte Jr D (1977) Relationship between plasma and cerebrospinal fluid insulin levels of dogs. Am J Physiol 233: E331-E334PubMedGoogle Scholar
  51. 51.
    Dziegielewska KM, Evans CAN, Malinowska DH, Møllgard K, Reynolds JM, Reynolds ML, Saunders NR (1979) Studies of the development of brain barrier systems to lipid insoluble molecules in fetal sheep. J Physiol (Lond) 292: 207–231CrossRefGoogle Scholar
  52. 52.
    Weindl A (1973) Neuroendocrine aspects of circumventricular organs. In: Ganong WF, Martini L (eds) Frontiers in neuroendocrinology, Oxford University Press, New York, p 3–32Google Scholar
  53. 53.
    Van Houten M, Posner BI, Kopriwa BM, Brawer JR (1980) Insulin binding sites localized to nerve terminals in rat median eminence and arcuate nucleus. Science 207: 1081–1083CrossRefPubMedGoogle Scholar
  54. 54.
    Van Houten M, Posner BI (1979) Insulin binds to brain blood vessels in vivo. Nature 282: 623–625CrossRefPubMedGoogle Scholar
  55. 55.
    Goldstein GW (1979) Relation of potassium transport to oxidative metabolism in isolated brain capillaries. J Physiol (Lond) 286: 185–195CrossRefGoogle Scholar
  56. 56.
    Betz AL, Gilboe DD, Yudilevich DL, Drewes LR (1973) Kinetics of unidirectional glucose transport into the isolated dog brain. Am J Physiol 225: 586–592PubMedGoogle Scholar
  57. 57.
    Thurston JH, Hauhart RE, Dirgo JA, McDougal Jr DB (1977) Insulin and brain metabolism. Absence of direct action of insulin on K+ and Na+ transport in normal rabbit brain. Diabetes 26: 1117–1119CrossRefPubMedGoogle Scholar
  58. 58.
    Daniel PM, Love ER, Pratt OE (1977) The influence of insulin upon the metabolism of glucose by the brain. Proc R Soc Lond [Biol] 196: 85–104CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 1981

Authors and Affiliations

  • W. M. Pardridge
    • 1
  1. 1.Department of Medicine, Division of Endocrinology and MetabolismUCLA School of MedicineLos AngelesUSA

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