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Mechanisms of blood-brain barrier breakdown

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Summary

The functional status of the blood-brain barrier (BBB) must be taken into account when designing and interpreting brain imaging techniques. The integrity of the BBB is affected in many diseases of the brain, with the potential involvement of a number of different but poorly understood cellular mechanisms. Factors known to disrupt the BBB experimentally include arachidonic acid and the eicosanoids, bradykinin, histamine and free radicals. These active compounds, released in pathological tissue, may alter cytosolic calcium levels and induce second messenger systems leading to an alteration in BBB permeability. Extravasation of plasma proteins may occurvia disrupted tight junctions, stimulation of fluid-phase vesicular transport or the formation of transcellular pores or channels.

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References

  1. Sage MR, Turski PA, Levin A (1989) CNS imaging and the brain barriers. In: Neuwelt EA (ed), Implications of the blood-brain barrier and its manipulations, vol 2. Plenum, New York London, pp 1–52

    Google Scholar 

  2. Bradbury MWB (1979) The concept of a blood-brain barrier. Wiley, New York

    Google Scholar 

  3. Abbott NJ, Bundgaard M, Cserr HF (1986) Comparative physiology of the blood-brain barrier. In: Suckling AJ, Rumsby MG, Bradbury MWB (eds) The blood-brain barrier in health and disease. Ellis Horwood, Chichester, pp 52–72

    Google Scholar 

  4. Begley DJ, Squires LK, Zlokovic BJ, Mitrovic SM, Hughes CCW, Revest PA, Greenwood J (1990) Permeability of the blood-brain barrier to the immunosuppresive cyclic peptide cyclosporin A J Neurochem 55:1222–1230

    Google Scholar 

  5. Cordon-Cardo C, O'Brien JP, Casals D, Rittman-Grauer L, Biedler JL, Mclamed MR, Bertino JR (1989) Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. Proc Natl Acad Sci USA 86:695–698

    Google Scholar 

  6. Ghersi-Egea JF, Minn A, Siest G (1988) A new aspect of the protective functions of the blood-brain barrier: activities of four drug-metabolizing enzymes in isolated rat brain microvessels. Life Sci 42:2515–2523

    Google Scholar 

  7. Klatzo I (1983) Disturbances of blood-brain barrier in cerebrovascular disorders. Acta Neuropathol (Berl) [Suppl] 8:81–88

    Google Scholar 

  8. Joo F (1987) A unifying concept on the pathogenesis of brain oedemas. Neuropathol Appl Neurobiol 13:161–176

    Google Scholar 

  9. Wahl M, Unterberg A, Baethmann A, Schilling L (1988) Mediators of blood-brain barrier dysfunction and formation of vasogenic brain edema. J Cereb Blood Flow Metab 8:621–634

    Google Scholar 

  10. Beck DW, Vinters HV, Hart MN, Cancilla PA (1984) Glial cells influence polarity of the blood-brain barrier. J Neuropathol Exp Neurol 43:219–224

    Google Scholar 

  11. Arthur FE, Shivers RR, Bowman PD (1987) Astrocyte-mediated induction of tight junctions in brain capillary endothelium: an efficient in vitro model. Dev Brain Res 36:155–159

    Google Scholar 

  12. Dehouck MP, Meresse S, Delorme P, Fruchart JC Cecchelli R, (1990) An easier, reproducible, and mass production method to study the blood-brain barrier in vitro. J Neurochem 54: 1798–1801

    Google Scholar 

  13. Greig NH (1989) Brain tumours and the blood-brain barrier. In: Neuwelt EA (ed) Implications of the blood-brain barrier and its manipulation, vol 2. Plenum, New York London, pp 77–106

    Google Scholar 

  14. Mei Liu H (1988) Neovasculature and blood-brain barrier in ischemic brain infarct. Acta Neuropathol (Berl) 75:422–426

    Google Scholar 

  15. Tsubaki SI, Brightman MW, Nakagawa H, Owens E, Blasberg RG (1987) Local blood flow and vascular permeability of autonomic ganglion-transplants in the brain. Brain Res 424:71–83

    Google Scholar 

  16. Schurer L, Temesvari P, Wahl M, Unterberg A, Baethmann A (1989) Blood-brain barrier permeability and vascular reactivity to bradykinin after pretreatment with dexamethasone. Acta Neuropathol (Berl) 77:576–581

    Google Scholar 

  17. Hollerhage HG, Walter GF, Stolke D (1989) Complementderived polypeptide C3adesArg as a mediator of inflammation at the blood-brain barrier in a new experimental cat model. Acta Neuropathol (Berl) 77:307–313

    Google Scholar 

  18. Dux E, Joo F (1982) Effects of histamine on brain capillaries. Fine structural and immunohistochemical studies after intracarotid infusion. Exp Brain Res 47:252–258

    Google Scholar 

  19. Olesen SP (1985) A calcium-dependent reversible increase in microvessels in frog brain induced by serotonin. J Physiol 361: 103–113

    Google Scholar 

  20. Black KL, Hoff JT (1985) Leukotrienes increase blood-brain barrier permeability following intraparenchymal injections in rats. Ann Neurol 18:349–351

    Google Scholar 

  21. Unterberg A, Wahl M, Hammersen F, Baethmann A (1987) Permeability and vasomotor response of cerebral vessels during exposure to arachidonic acid. Acta Neuropathol (Berl) 73: 209–219

    Google Scholar 

  22. Kempski O, Villacara A, Spatz M, Dodson RF, Corn C, Merkel N, Bembry J (1987) Cerebromicrovascular endothelial permeability. In vitro studies. Acta Neuropathol (Berl) 74:329–334

    Google Scholar 

  23. Olesen SP (1987) Free oxygen radicals decrease electrical resistance of microvascular endothelium in brain. Acta Physiol Scand 129:181–188

    Google Scholar 

  24. Moore SA, Figard PH, Spector AA, Hart N (1989) Brain microvessels produce 12-hydroxyeicosatetraenoic acid. J Neurochem 53:376–382

    Google Scholar 

  25. Dietrich WD, Prado R, Watson BD, Nakayama H (1988) Middle cerebral artery thrombosis: acute blood-brain barrier consequences. J Neuropathol Exp Neurol 47:443–451

    Google Scholar 

  26. Dietrich WD, Prado R, Watson BD (1988) Photochemically stimulated blood-borne factors induce blood-brain barrier alterations in rats. Stroke 19:857–862

    Google Scholar 

  27. Koenig H, Goldstone AD, Lu CY (1989) Polyamines mediate the reversible opening of the blood-brain barrier by the intracarotid infusion of hyperosmolal mannitol. Brain Res 483:110–116

    Google Scholar 

  28. Koenig H, Goldstone AD, Lu CY, Trout JJ (1989) Polyamines and Ca2+ mediate opening of the blood-brain barrier: in vitro studies in isolated rat cerebral capillaries. J Neurochem 52: 1135–1142

    Google Scholar 

  29. Koenig H, Goldstone AD, Lu CY (1989) Blood-brain barrier breakdown in cold-injured brain is linked to a biphasic stimulation of ornithine decarboxylase activity and polyamine synthesis: Both are coordinately inhibited by verapamil, dexamethasone, and aspirin. J Neurochem 52:101–109

    Google Scholar 

  30. Trout JJ, Koenig H, Goldstone A, Lu CY (1986) Blood-brain barrier breakdown by cold injury. Polyamine signals mediate acute stimulation of endocytosis, vesicular transport, and microvillus formation in rat cerebral capillaries. Lab Invest 55: 622–631

    Google Scholar 

  31. Olesen SP (1987) Regulation of ion permeability in frog brain venules. Significance of calcium, cyclic nucleotides and protein kinase C. J Physiol 387:59–68

    Google Scholar 

  32. Rubin LL, Barbu K, Bard F, Cannon C, Hall DE, Horner H, Janatpour M, Liaw C, Manning K, Morales J, Porter S, Tanner L, Tomaselli K, Yednock T (1991) Differentiation of brain endothelial cells in cell culture. Ann N Y Acad Sci (in press)

  33. Klatzo I (1987) Pathophysiological aspects of brain edema. Ata Neuropathol (Berl) 72:236–239

    Google Scholar 

  34. Pappius HM (1989) Cereral edema and the blood-brain barier. In: Neuwelt EA (ed) Implications of the blood-brain barrier and its manipulations, vol 2. Plenum, New York London, pp 293–309

    Google Scholar 

  35. Ohnishi T, Sher PB, Posner JB, Shapiro WR (1990) Capillary permeability factor secreted by malignant brain tumor. J Neurosurg 72:245–251

    Google Scholar 

  36. Luthert PJ, Greenwood J, Lantos PL, Pratt OE (1986) The effects of dexamethasone on vascular permeability of experimental brain tumours. Acta Neuropathol (Berl) 69:288–294

    Google Scholar 

  37. Yamada K, Ushio Y, Hayakawa T, Arita N, Yamada N, Mogami H (1983) Effects of methylprednisolone on peritumoral brain edema. J Neurosurg 59:612–619

    Google Scholar 

  38. Hossmann K-A, Hurter T Oschlies U (1983) The effect of dexamethasone on serum protein extravasation and edema development in experimental brain tumors of cat. Acta Neuropathol (Berl) 60:223–231

    Google Scholar 

  39. Jarden JO, Dhawan V, Poltorak A, Posner JB, Rottenberg DA (1985) Positron emission tomographic measurement of blood-to-brain and blood-to-tumor transport of82Rb: The effect of dexamethasone and whole brain radiation therapy. Ann Neurol 18: 636–646

    Google Scholar 

  40. Luthert PJ, Greenwood J (1989) Experimental studies and the blood-brain barrier. In: Capildeo R (ed) Steroids in diseases of the central nervous system. Wiley, New York, pp 47–57

    Google Scholar 

  41. Neuwelt EA, Barnett PA (1989) Blood-brain barrier disruption in the treatment of brain tumours: animal studies. In: Neuwelt EA (ed) Implications of the blood-brain barrier and its manipulations, vol 2. Plenum, New York London pp 107–194

    Google Scholar 

  42. Neuwelt EA, Dahlborg SA (1989) Blood-brain barrier disruption in the treatment of brain tumours: clinical implications. In: Neuwelt EA (ed) Implications of the blood-brain barrier and its manipulations, vol 2. Plenum, New York London, pp 195–262

    Google Scholar 

  43. Brinker RA (1979) Neuroangiographic contrast agents. In: Miller RE, Skucas J (eds) Radiographic contrast agents. University Park Press Baltimore, pp 365–374

    Google Scholar 

  44. Waldron RL, Brayn RN (1975) Effect of contrast agents on the blood-brain barrier: an electron microscopic study. Radiology 116:195–198

    Google Scholar 

  45. Suzuki M, Iwasaki Y, Yamamoto T, Konno H, Kudo H (1988) Sequelae of the osmotic blood-brain barrier opening in rats. J Neurosurg 69:421–428

    Google Scholar 

  46. Lantos G (1989) Cortical blindness due to osmotic disruption of the blood-brain barrier by angiographic contrast material: CT and MRI studies. Neurology 39:567–571

    Google Scholar 

  47. Nagy Z, Szabo M, Huttner I (1985) Blood-brain barrier impairement by low pH buffer perfusion via the internal carotid artery in the rat. Acta Neuropathol (Berl) 68:160–163

    Google Scholar 

  48. Paljaryi L, Rehncrona S, Soderfeldt B, Olsson Y, Kalimo H (1983) Brain lactic acidosis and ischemic cell damage: Quantitative ultrastructural changes in capillaries of rat cerebral cortex. Acta Neuropathol (Berl) 60:232–240

    Google Scholar 

  49. Petito CK, Schaefer JA, Plum F (1977) Ultrastructural characteristics of the brain and blood-brain barrier in experimental seizures. Brain Res 127:251–267

    Google Scholar 

  50. Westergaard E (1977) The blood-brain barrier to horseradish peroxidase under normal and experimental conditions. Acta Neuropathol (Berl) 39:181–187

    Google Scholar 

  51. Kuroiwa T, Ting P, Martinez H, Klatzo I (1985) The biphasic opening of the blood-brain barrier to proteins following temporary middle cerebral artery occlusion. Acta Neuropathol (Berl) 68:122–129

    Google Scholar 

  52. Greenwood J, Hazell AS, Luthert PJ (1989) The effect of a low pH saline perfusate upon the integrity of the energy depleted blood-brain barrier. J Cereb Blood Flow Metab 9:234–242

    Google Scholar 

  53. Daniel PM, Lam DKC, Pratt OE (1981) Changes in the effectiveness of the blood-brain and blood-spinal cord barriers in experimental allergic encephalomyelitis. J Neurol Sci 52:211–219

    Google Scholar 

  54. Juhler M (1988) Pathophysiological aspects of acute experimental allergic encephalomyelitis. Acta Neurol Scand 78: Suppl 119

  55. Juhler M, Neuwelt EA (1989) The blood-brain barrier and the immune system. In: Neuwelt EA (ed), Implications of the blood-brain barrier and its manipulation, vol 1. Plenum, New York London, pp 389–410

    Google Scholar 

  56. Hawkins CP, Munro PMG, Mackenzie F, Kesselring, J, Tofts PS, Du Boulay EPGH, Landon DN, McDonald WI (1990) Duration and selectivity of blood-brain barrier breakdown in chronic relapsing experimental allergic encephalomyelitis studied by gadolium-DTPA and protein markers. Brain 113:365–378

    Google Scholar 

  57. Hawkins CP, Landon DN, Mackenzie F, McDonald WI, Munro PMG (1990) Studies on the mechanism of blood-brain barrier breakdown in chronic relapsing experimental allergic encephalomyelitis in the guinea-pig: J Physiol 426:116P

    Google Scholar 

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  1. Department of Clinical Science, Institute of Ophthalmology, London, UK

    J. Greenwood

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Greenwood, J. Mechanisms of blood-brain barrier breakdown. Neuroradiology 33, 95–100 (1991). https://doi.org/10.1007/BF00588242

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