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Cellular and Molecular Neurobiology

, Volume 20, Issue 2, pp 217–230 | Cite as

Osmotic Opening of the Blood–Brain Barrier: Principles, Mechanism, and Therapeutic Applications

  • Stanley I. Rapoport
Article

Abstract

1. Osmotic opening of the blood–brain barrier by intracarotid infusion of a hypertonic arabinose or mannitol solution is mediated by vasodilatation and shrinkage of cerebrovascular endothelial cells, with widening of the interendothelial tight junctions to an estimated radius of 200 Å. The effect may be facilitated by calcium-mediated contraction of the endothelial cytoskeleton.

2. The marked increase in apparent blood–brain barrier permeability to intravascular substances (10-fold for small molecules) following the osmotic procedure is due to both increased diffusion and bulk fluid flow across the tight junctions. The permeability effect is largely reversed within 10 min.

3. In experimental animals, the osmotic method has been used to grant wide access to the brain of water-soluble drugs, peptides, antibodies, boron compounds for neutron capture therapy, and viral vectors for gene therapy. The method also has been used together with anticancer drugs to treat patients with metastatic or primary brain tumors, with some success and minimal morbidity.

arabinose mannitol blood–brain barrier brain drug chemotherapy osmosis shrinkage permeability tumor bulk flow tight junctions capillary 

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REFERENCES

  1. Abbott, N. J., and Revest, P. A. (1991). Control of brain endothelial permeability. Cerebrovasc. Brain Metab. Rev. 3:39-72.Google Scholar
  2. Armstrong, B. K., Robinson, P. J., and Rapoport, S. I. (1987). Size-dependent blood-brain barrier opening demonstrated with [14C]sucrose and a 200,000-Da [3H]dextran. Exp. Neurol. 97:686-696.Google Scholar
  3. Armstrong, B. K., Smith, Q. R., Rapoport, S. I., Strohalm, J., Kopecek, J., and Duncan, R. (1989). Osmotic opening of the blood-brain barrier permeability to n-(2-hydroxypropyl) methacrylamide copolymers. Effect of polymer Mw, charge and hydrophobicity. J. Control. Release 10:27-35.Google Scholar
  4. Barranger, J. A., Rapoport, S. I., Fredericks, W. R., Pentchev, P. G., MacDermot, K. D., Steusing, J. K., and Brady, R. O. (1979). Modification of the blood-brain barrier: Increased concentration and fate of enzymes entering the brain. Proc. Natl. Acad. Sci. USA 76:481-485.Google Scholar
  5. Barth, R. F., Yang, W., Rotaru, J. H., Moeschberger, M. L., Joel, D. D., Nawrocky, M. H., Goodman, J. H., and Soloway, A. H. (1997). Boron neutron capture therapy of brain tumors: Enhanced survival following intracarotid injection of either sodium borocaptate or boronophenylalanine with or without blood-brain barrier disruption. Cancer Res. 57:1129-1136.Google Scholar
  6. Brightman, M. W., Hori, M., Rapoport, S. I., Reese, T. S., and Westergaard, E. (1973). Osmotic opening of tight junctions in cerebral endothelium. J. Comp. Neurol. 152:317-325.Google Scholar
  7. Brownson, E. A., Abbruscato, T. J., Gillespie, T. J., Hruby, V. J., and Davis, T. P. (1994). Effect of peptidases at the blood brain barrier on the permeability of enkephalin. J. Pharmacol. Exp. Ther. 270:675-680.Google Scholar
  8. Chamberlain, M. C., Murovic, J. S., and Levin, V. A. (1988). Absence of contrast enhancement on CT brain scans of patients with supratentorial malignant gliomas. Neurology 38:1371-1374.Google Scholar
  9. Chi, O. Z., Lu, X., Wei, H. M., Williams, J. A., and Weiss, H. R. (1996). Hydroxyethyl starch solution attenuates blood-brain barrier disruption caused by intracarotid injection of hyperosmolar mannitol in rats. Anesth. Analg. 83:336-341.Google Scholar
  10. Chi, O. Z., Chang, Q., Wang, G., and Weiss, H. R. (1997). Effects of nitric oxide on blood-brain barrier disruption caused by intracarotid injection of hyperosmolar mannitol in rats. Anesth. Analg. 84:370-375.Google Scholar
  11. Chiueh, C. C., Sun, C. L., Kopin, I. J., Fredericks, W. R., and Rapoport, S. I. (1978). Entry of [3H]norepinephrine, [125I]albumin and Evans blue from blood into brain following unilateral osmotic opening of the blood-brain barrier. Brain Res. 145:292-301.Google Scholar
  12. Collander, R. (1937). The permeability of plant protoplasts to non-electrolytes. Trans. Faraday Soc. 33:985-990.Google Scholar
  13. Cosolo, W. C., Martinello, P., Louis, W. J., and Christophidis, N. (1989). Blood-brain barrier disruption using mannitol: Time course and electron microscopic studies. Am. J. Physiol. 256:R443-R447.Google Scholar
  14. Crossen, J. R., Goldman, D. L., Dahlborg, S. A., and Neuwelt, E. A. (1992). Neuropsychological assessment outcomes of nonacquired immunodeficiency syndrome patients with primary central nervous system lymphoma before and after blood-brain barrier disruption chemotherapy. Neurosurgery 30:23-29.Google Scholar
  15. Dahlborg, S. A., Henner, W. D., Crossen, J. R., Tableman, M., Petrillo, A., Braziel, R., and Neuwelt, E. A. (1996). Non-AIDS primary CNS lymphoma: The first example of a durable response in a primary brain tumor using enhanced chemotherapy delivery without cognitive loss and without radiotherapy. Cancer J. Sci. Am. 2:166-174.Google Scholar
  16. DeAngelis, L. M. (1993). Cerebral lymphoma presenting as a nonenhancing lesion on a computed tomographic/magnetic resonance scan. Ann. Neurol. 33:308-311.Google Scholar
  17. Dehouck, B., Fenart, L., Dehouck, M.-P., Pierce, A., Torpier, G., and Cecchelli, R. (1997). A new function of the LDL receptor: Transcytosis of LDL through blood-brain barrier. J. Cell Biol. 138:877-889.Google Scholar
  18. Dorovini-Zis, K., Sato, M., Goping, G., Rapoport, S. I., and Brightman, M. (1983). Ionic lanthanum passage across cerebral endothelium exposed to hyperosmotic arabinose. Acta Neuropathol. (Berlin) 60:49-60.Google Scholar
  19. Dorovini-Zis, K., Bowman, P. D., Betz, A. L., and Goldstein, G. W. (1984). Hyperosmotic arabinose solutions open tight junctions between brain capillary endothelial cells in tissue culture. Brain Res. 302:383-386.Google Scholar
  20. Fenstermacher, J. D., and Johnson, J. A. (1966). Filtration and reflection coefficients of the rabbit bloodbrain barrier. Am. J. Physiol. 211:341-346.Google Scholar
  21. Fishman, J. B., Rubin, J., 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.Google Scholar
  22. Friden, P. M., Walus, L. R., Musso, G. F., Taylor, M. A., Malfroy, B., and Starzyk, R. M. (1991). Anti-transferrin receptor antibody and antibody-drug conjugates cross the blood-brain barrier. Proc. Natl. Acad. Sci. USA 88:4771-4775.Google Scholar
  23. Friden, P. M., Walus, L. R., Watson, P., Doctrow, S. R., Kozarich, J. W., Bäckman, C., Bergman, H., Hoffer, B., Bloom, F., and Granholm, A.-C. (1993). Blood-brain barrier penetration and in vivo activity of an NGF conjugate. Science 259:373-377.Google Scholar
  24. Gjedde, A., Reith, J., Léger, G., Cumming, P., Yasuhara, Y., Guttman, M., and Kuwabara, H. (1995). Blood-brain barrier removal of DOPA: Role in regulation of dopamine synthesis and treatment of Parkinson's disease. In Greenwood, J., Begley, D., and Segal, M. (eds.), New Concepts of a Blood-Brain Barrier, Plenum Press, London, pp. 103-109.Google Scholar
  25. Greig, N. H., Fredericks, W. R., Holloway, H. W., Soncrant, T. T., and Rapoport, S. I. (1988). Delivery of interferon-alpha to brain by transient osmotic blood-brain barrier modification in the rat. J. Pharmacol. Exp. Ther. 245:581-586.Google Scholar
  26. Gumbiner, B. M. (1996). Cell adhesion: The molecular basis of tissue architecture and morphogenesis. Cell 84:345-357.Google Scholar
  27. Gumerlock, M. K., and Neuwelt, E. A. (1990). The effects of anesthesia on osmotic blood-brain barrier disruption. Neurosurgery 26:268-277.Google Scholar
  28. Gumerlock, M. K., Belshe, B. D., Madsen, R., and Watts, C. (1992). Osmotic blood-brain barrier disruption and chemotherapy in the treatment of high grade malignant glioma: Patient series and literature review. J. Neurooncol. 12:33-46.Google Scholar
  29. Gumerlock, M. K., York, D., and Durkis, D. (1994). Visual evoked responses as a monitor of intracranial pressure during hyperosmolar blood-brain barrier disruption. Acta Neurochir. Suppl. 60:132-135.Google Scholar
  30. Hicks, J. T., Albrecht, P., and Rapoport, S. I. (1976). Entry of neutralizing antibody to measles into brain and cerebrospinal fluid of immunised momkeys following osmotic opening of the blood-brain barrier. Exp. Neurol. 53:768-779.Google Scholar
  31. Hiesiger, E. M., Voorhies, R. M., Basler, G. A., Lipscuhtz, L. E., Posner, J. B., and Shapiro, W. R. (1986). Opening the blood-brain and blood-tumor barriers in experimental rat brain tumor: the effect of intracarotid hyperosmolar mannitol on capillary permeability and blood flow. Ann. Neurol. 19:50-59.Google Scholar
  32. Inamura, T., Nomura, T., Bartus, R. T., and Black, K. L. (1994). Intracarotid infusion of RMP-7, a bradykinin analog: A method for selective drug delivery to brain tumors. J. Neurosurg. 81:752-758.Google Scholar
  33. Jena, M., Minore, J. F., and O'Neill, W. C. (1997). A volume-sensitive, IP3-insensitive Ca2+ store in vascular endothelial cells. Am. J. Physiol. 273:C316-C322.Google Scholar
  34. Jiao, S., Miller, P. J., and Lapchak, P. A. (1996). Enhanced delivery of [125I]glial cell line-derived neurotrophic factor to the rat CNS following osmotic blood-brain barrier modification. Neurosci. Lett. 220:187-190.Google Scholar
  35. Kessler, R. M., Goble, J. C., Bird, J. H., Girton, M. E., Doppman, J. L., Rapoport, S. L., and Barranger, J. A. (1984). Measurement of blood-brain barrier permeability with positron emission tomography and [68Ga]EDTA. J. Cereb. Blood Flow Metab. 4:323-328.Google Scholar
  36. Latker, C. H., Lynch, K. J., Shinowara, N. L., and Rapoport, S. I. (1986). The morphology of pial blood vessels of the frog, preserved by rapid freezing and freeze substitution. Brain Res. 375:186-192.Google Scholar
  37. Levine, R. L., Fredericks, W. R., and Rapoport, S. I. (1985). Clearance of bilirubin from rat brain after reversible osmotic opening of the blood-brain barrier. Pediatr. Res. 19:1040-1043.Google Scholar
  38. Lin, W. L. (1988). Leakage of blood-retinal barrier due to damaging effect of protamine sulfate on the endothelium. Acta Neuropathol. (Berl.) 76:427-431.Google Scholar
  39. Lin, W., Paczynski, R. P., Kuppusamy, K., Hsu, C. Y., and Haacke, E. M. (1997). Quantitative measurements of regional cerebral blood volume using MRI in rats: effects of arterial carbon dioxide tension and mannitol. Magn. Reson. Med. 38:420-428.Google Scholar
  40. Lowenstein, P. R., Morrison, E. E., Bain, D., Hodge, P., Preston, C. M., Clissold, P., Stow, N. D., Mckee, T. A., and Castro, M. G. (1994). Use of recombinant vectors derived from herpes simplex virus 1 mutant tsK for short-term expression of transgenes encoding cytoplasmic and membrane anchored proteins in postmitotic polarized cortical neurons and glial cells in vitro. Neuroscience 60:1059-1077.Google Scholar
  41. Millay, R. H., Klein, M. L., Shults, W. T., Dahlborg, S. A., and Neuwelt, E. A. (1986). Maculopathy associated with combination chemotherapy and osmotic opening of the blood-brain barrier. Am. J. Ophthalmol. 102:626-632.Google Scholar
  42. Muldoon, L. L., Nilaver, G., Kroll, R. A., Pagel, M. A., Breakefield, X. O., Chiocca, E. A., Davidson, B. L., Weissleder, R., and Neuwelt, E. A. (1995). Comparison of intracerebral inoculation and osmotic blood-brain barrier disruption for delivery of adenovirus, herpesvirus, and iron oxide particles to normal rat brain. Am. J. Pathol. 147:1840-1851.Google Scholar
  43. Nag, S. (1995). Role of the endothelial cytoskeleton in blood-brain barrier permeability to protein. Acta Neuropathol. (Berl.) 90:454-460.Google Scholar
  44. Nagashima, T., Shijing, W., Mizoguchi, A., and Tamaki, N. (1994). A possible role of calcium ion in osmotic opening of blood-brain barrier. J. Auton. Nerv. Syst. 49 (Suppl.):S145-S149.Google Scholar
  45. Neuwelt, E. A., Frenkel, E. P., Diehl, J., Vu, L. H., Rapoport, S. I., and Hill, S. A. (1980). Reversible osmotic blood-brain barrier disruption in humans: Implication for the chemotherapy of malignant brain tumors, Neurosurgery 7:44-52.Google Scholar
  46. Neuwelt, E. A., Glasberg, M., Frenkel, E., and Barnett, P. (1983). Neurotoxicity of chemotherapeutic agents after blood-brain barrier modification: Neuropathological studies. Ann. Neurol. 14:316-324.Google Scholar
  47. Neuwelt, E. A., Barnett, P. A., Hellstrom, I., Hellstrom, K. E., Beaumier, P., McCormick, C. I., and Weigel, R. M. (1988). Delivery of melanoma-associated immunoglobulin monoclonal antibody and Fab fragments to normal brain utilizing osmotic blood-brain barrier disruption. Cancer Res. 48:4725-4729.Google Scholar
  48. Neuwelt, E. A., Dahlborg, S. A., Goldman, D., Dana, B., and Ramsey, F. L. (1989). Significant prolongation of survival of primary CNS lymphoma patients by combination chemotherapy given in association with osmotic blood-brain barrier disruption. Proc. Am. Assoc. Cancer Res. 30:264.Google Scholar
  49. Neuwelt, E. A., Williams, P. C., Mickey, B. E., Frenkel, E. P., and Henner, W. D. (1994). Therapeutic dilemma of disseminated CNS germinoma and the potential of increased platinum-based chemotherapy delivery with osmotic blood-brain barrier disruption. Pediatr. Neurosurg. 21:16-22.Google Scholar
  50. Neuwelt, E. A., Brummett, R. E., Remsen, L. G., Kroll, R. A., Pagel, M. A., McCormick, C. I., Guitjens, S., and Muldoon, L. L. (1996). In vitro and animal studies of sodium thiosulfate as a potential chemoprotectant against carboplatin-induced ototoxicity. Cancer Res. 56:706-709.Google Scholar
  51. Ohata, M., Fredericks, W. R., Neuwelt, E. A., Sundaram, U., and Rapoport, S. I. (1985). [3H]Methotrexate loss from the rat brain following enhanced uptake by osmotic opening of the blood-brain barrier. Cancer Res. 45:1092-1096.Google Scholar
  52. Ohno, K., Pettigrew, K. D., and Rapoport, S. I. (1978). Lower limits of cerebrovascular permeability to nonelectrolytes in the conscious rat. Am. J. Physiol. 235:H299-H307.Google Scholar
  53. Oike, M., Droogmans, G., and Nilius, B. (1994). Mechanosensitive Ca2+ transients in endothelial cells from human umbilical vein. Proc. Natl. Acad. Sci. USA 91:2940-2944.Google Scholar
  54. Okisaka, S., Kuwabara, T., and Rapoport, S. I. (1974). Selective destruction of the pigmented epithelium in the ciliary body of the eye. Science 184:1298-1299.Google Scholar
  55. Olesen, S. P. (1987). Regulation of ion permeability in frog brain venules. Significance of calcium, cyclic nucleotides and protein kinase C. J. Physiol. (Lond.) 387:59-69.Google Scholar
  56. Overton, E. (1895). Ñber die osmotischen Eigenschaften der lebenden Pflanzen und Tierzelle. Vierteljahresschr. Naturforsch. Ges. Zurich 40:159-201.Google Scholar
  57. Pastan, I., Willingham, M. C., and Gottesman, M. (1991). Molecular manipulations of the multidrug transporter: A new role for transgenic mice. FASEB J. 5:2523-2528.Google Scholar
  58. Rapoport, S. I. (1970). Effect of concentrated solutions on blood-brain barrier. Am. J. Physiol. 219:270-274.Google Scholar
  59. Rapoport, S. I. (1976). Blood-Brain Barrier in Physiology and Medicine, Raven Press, New York, p. 316.Google Scholar
  60. Rapoport, S. I. (1988). Osmotic opening of the blood-brain barrier. Ann. Neurol. 24:677-680.Google Scholar
  61. Rapoport, S. I. (1991). Microinfarction: Osmotic BBB opening of microcrystals in infusate? J. Neurosurg. 74:685.Google Scholar
  62. Rapoport, S. I. (1996). Modulation of blood-brain barrier permeability. J. Drug Target. 3:417-425.Google Scholar
  63. Rapoport, S. I. (1997). Brain edema and the blood-brain barrier. In Welch, K. M. A., Caplan, L. R., Reis, D. J., Siesjö, B. K., and Weir, B. (eds.), Primer on Cerebrovascular Diseases, Academic Press, New York, pp. 25-28.Google Scholar
  64. Rapoport, S. I., and Robinson, P. J. (1986). Tight-junctional modification as the basis of osmotic opening of the blood-brain barrier. Ann. N.Y. Acad. Sci. 481:250-267.Google Scholar
  65. Rapoport, S. I., and Robinson, P. J. (1990). A therapeutic role for osmotic opening of the blood-brain barrier. Re-evaluation of literature and of importance of source-sink relations between brain and tumor. In Johanson, B. B., Owman, C., and Widner, H. (eds.), Pathophysiology of the Blood-Brain Barrier, Long Term Consequences of Barrier Dysfunction for the Brain, Elsevier, Amsterdam, pp. 167-181.Google Scholar
  66. Rapoport, S. I., and Thompson, H. K. (1973). Osmotic opening of the blood-brain barrier in the monkey without associated neurological deficits. Science 180:971.Google Scholar
  67. Rapoport, S. I., Hori, M., and Klatzo, I. (1972). Testing of a hypothesis for osmotic opening of the blood-brain barrier. Am. J. Physiol. 223:323-331.Google Scholar
  68. Rapoport, S. I., Fredericks, W. R., Ohno, K., and Pettigrew, K. D. (1980). Quantitative aspects of reversible osmotic opening of the blood-brain barrier. Am. J. Physiol. 238:R421-R431.Google Scholar
  69. Rapoport, S. I., Fitzhugh, R., Pettigrew, K. D., Sundaram, U., and Ohno, K. (1982). Drug entry into and distribution within brain and cerebrospinal fluid: 14C-Urea pharmacokinetics. Am. J. Physiol. 242:R339-R348.Google Scholar
  70. Ravussin, P., Archer, D. P., Tyler, J. L., Meyer, E., Abou-Madi, M., Diksic, M., Yamamoto, L., and Trop, D. (1986). Effects of rapid mannitol infusion on cerebral blood volume. A positron emission tomographic study in dogs and man. J. Neurosurg. 64:104-113.Google Scholar
  71. Reese, T. S., and Karnovsky, M. J. (1967). Fine structural localization of a blood-brain barrier to exogenous peroxidase. J. Cell Biol. 34:207-217.Google Scholar
  72. Robinson, P. J., and Rapoport, S. I. (1987). Size selectivity of blood-brain barrier permeability at various times after osmotic opening. Am. J. Physiol. 253:R459-R466.Google Scholar
  73. Robinson, P. J., and Rapoport, S. I. (1990). Model for drug uptake by brain tumors: Effects of osmotic treatment and of diffusion in brain. J. Cereb. Blood Flow Metab. 10:153-161.Google Scholar
  74. Rosomoff, H. L. (1962). Distribution of intracranial contents after hypertonic urea. J. Neurosurg. 19:859-864.Google Scholar
  75. Salahuddin, T. S., Johansson, B. B., Kalimo, H., and Olsson, Y. (1988). Structural changes in the rat brain after carotid infusions of hyperosmolar solutions. An electron microscopic study. Acta Neuropathol. (Berl.) 77:5-13.Google Scholar
  76. Sanovich, E., Bartus, R. T., Friden, P. M., Dean, R. L., Le, H. Q., and Brightman, M. (1995). Pathway across blood-brain barrier opened by the bradykinin agonist, RMP-7. Brain Res. 705:125-135.Google Scholar
  77. Schinkel, A. H., Smit, J. J., van Telligen, O., Beijnen, J. H., Wagenaar, E., van Deemter, L., Mol, C. A. A. M., van der Valk, M. A., Robanus-Maandag, E. C., De Riele, H. P. J., Berns, A. J. M., and Borst, P. (1994). Disruption of the mouse mdrla P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell 77:491-502.Google Scholar
  78. Smith, Q. R. (1993). Drug delivery to brain and the role of carrier-mediated transport. Adv. Exp. Med. Biol. 331:83-93.Google Scholar
  79. Staddon, J. M., and Rubin, L. L. (1996). Cell adhesion, cell junctions and the blood-brain barrier. Curr. Opin. Neurobiol. 6:622-627.Google Scholar
  80. Suzuki, M., Iwasaki, Y., Yamamoto, T., Konno, H., and Kudo, H. (1988). Sequelae of the osmotic bloodbrain barrier opening in rats. J. Neurosurg. 69:421-428.Google Scholar
  81. Takada, T., Vistica, D. T., Greig, N. H., Purdon, D., Rapoport, S. I., and Smith, Q. R. (1992). Rapid high-affinity transport of a chemotherapeutic amino acid across the blood-brain barrier. Cancer Res. 52:2191-2196.Google Scholar
  82. Takahashi, M., Tsutsui, H., Murayama, C., Miyazawa, T., and Fritz-Zieroth, B. (1996). Neurotoxicity of gadolinium contrast agents for magnetic resonance imaging in rats with osmotically disrupted blood-brain barrier. Magn. Reson. Imaging 14:619-623.Google Scholar
  83. Tator, C. H. (1972). Chemotherapy of brain tumors: uptake of tritiated methotrexate by a transplantable intracerebral ependymoblastoma in mice. J. Neurosurg. 37:1-8.Google Scholar
  84. Tomiwa, K., Hazama, F., and Mikawa, H., (1982). Reversible osmotic opening of the blood-brain barrier: Prevention of tissue damage with filtration of the perfusate. Acta Pathol. Jpn. 32:427-435.Google Scholar
  85. Tomiwa, K., Hazama, F., and Mikawa, H. (1983). Neurotoxicity of vincristine after the osmotic opening of the blood-brain barrier. Neuropathol. Appl. Neurobiol. 9:345-354.Google Scholar
  86. Walker, M. (1977). Treatment of brain tumors. Med. Clin. North Am. 61:1045-1051.Google Scholar
  87. Warnke, P. C., Blasberg, R. G., and Groothuis, D. R. (1987). The effect of hyperosmotic blood-brain barrier disruption on blood-to-tissue transport in ENU-induced gliomas. Ann. Neurol. 22:300-305.Google Scholar
  88. Westergren, I., and Johansson, B. B. (1993). Altering the blood-brain barrier in the rat by intracarotid infusion of polycations: A comparison between protamine, poly-L-lysine and poly-L-arginine. Acta Physiol. Scand. 149:99-104.Google Scholar
  89. Wielbo, D., Sernia, C., Gyurko, R., and Phillips, M. I. (1995). Antisense inhibition of hypertension in the spontaneously hypertensive rat. Hypertension 25:314-319.Google Scholar
  90. Williams, P. C., Henner, W. D., Roman-Goldstein, S., Dahlborg, S. A., Brummett, R. E., Tableman, M., Dana, B. W., and Neuwelt, E. A. (1995). Toxicity and efficacy of carboplatin and etoposide in conjunction with disruption of the blood-brain tumor barrier in the treatment of intracranial neoplasms. Neurosurgery 37:17-28.Google Scholar
  91. Williams, W. M., Chang, M. C., and Rapoport, S. I. (1994). Cerebral microvessel phospholipase A2 activity in senescent mouse. Neurochem. Res. 19:317-320.Google Scholar
  92. Wong, A. J., and Gotleib, A. I. (1986). Endothelial cell monolayer integrity. I. Characterization of dense peripheral band of microfilaments. Arteriosclerosis 6:212-219.Google Scholar
  93. Yang, W., Barth, R. F., Carpenter, D. P., Moeschberger, M. L., and Goodman, J. H. (1996). Enhanced delivery of boronophenylalanine for neutron capture therapy by means of intracarotid injection and blood-brain barrier disruption. Neurosurgery 38:965-992.Google Scholar
  94. Ziylan, Y. Z., Robinson, P. J., and Rapoport, S. I. (1983). Differential blood-brain barrier permeabilities to 14C-sucrose and 3H-inulin after osmotic opening in the rat. Exp. Neurol. 79:845-857.Google Scholar
  95. Ziylan, Y. Z., Robinson, P. J., and Rapoport, S. I. (1984). Blood-brain barrier permeability to sucrose and dextran after osmotic opening. Am. J. Physiol. 247:R634-R638.Google Scholar
  96. Zlokovic, B. V., and Apuzzo, M. L. J. (1997). Cellular and molecular neurosurgery: Pathways from concept to reality-Part II: Vector systems and delivery methodologies for gene therapy of the central nervous system. Neurosurgery 40:805-813.Google Scholar
  97. Zunkeler, B., Carson, R. E., Olson, J., Blasberg, R. G., Girton, M., Bacher, J., Herscovitch, P., and Oldfield, E. H. (1996a). Hyperosmolar blood-brain barrier disruption in baboons: An in vivo study using positron emission tomography and rubidium-82. J. Neurosurg. 84:494-502.Google Scholar
  98. Zunkeler, B., Carson, R. E., Olson, J., Blasberg, R. G., DeVroom, H., Lutz, R. J., Saris, S. C., Wright, D. C., Kammerer, W., Patronas, N. J., Dedrick, R. L., Herscovitch, P., and Oldfield, E. H. (1996b). Quantification and pharmacokinetics of blood-brain barrier disruption in humans. J. Neurosurg. 85:1056-1065.Google Scholar

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© Plenum Publishing Corporation 2000

Authors and Affiliations

  • Stanley I. Rapoport
    • 1
  1. 1.Section on Brain Physiology and MetabolismNational Institute on Aging, National Institutes of HealthBethesda

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