Skip to main content
SpringerLink
Log in

Metabolically dependent blood-brain barrier breakdown in chronic relapsing experimental allergic encephalomyelitis

  • Regular Papers
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

Summary

We have studied chronic relapsing experimental allergic encephalomyelitis (CREAE), a model of immune-mediated demyelination, using gadolinium (Gd)-enhanced magnetic resonance imaging in vivo and the bood-brain barrier (BBB) markers, lanthanum nitrate and Gd nitrate, histologically. In regions of the spinal cord showing Gd enhancement, there was evidence for vesicular transport as a mechanism of BBB breakdown in CREAE, shown by an increased number of endiothelial vesicles containing lanthanide (lanthanum or Gd, whichever had been perfused) and deposition of tracer in the perivascular space; tight interendothelial junctions remained intact. Prior perfusion with 2,4-dinitrophenol, a metabolic inhibitor, suppressed the appearance of endothelial vesicles containing lanthanide and tracer in the perivascular space. We conclude that an important contribution to BBB breakdown in CREAE is mediated by a metabolic change in the endothelial cells associated with increased vesicular transport.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Bradbury M (1979) The concept of a blood-brain barrier. Wiley, Chichester, pp 351–382

    Google Scholar 

  2. Broadwell RD (1989) Transcytosis of macromolecules through the blood-brain barrier: cell biooogical perspective and critical appraisal. Acta Neuropathol 79:117–128

    Google Scholar 

  3. Brosnan CF, Selmaj K, Raine CS (1988) Hypothesis: a role for tumour necrosis factor in immune-mediated demyelination and its relevance to multiple sclerosis. J Neuroimmunol 18:87–94

    Google Scholar 

  4. Brown WJ (1978) The capillaries in acute and subacute multiple sclerosis — a morphometric analysis. Neurology 28:84–92

    Google Scholar 

  5. Cervos-Navarro J, Artigas J, Mrsulja BJ (1983) Morphofunctional aspects of the normal and pathological blood-brain barrier. Acta Neuropathol [Suppl VIII]:1–19

  6. Claudio L, Kress Y, Norton WT, Brosnan CF (1989) Increased vesicular transport and decreased mitochondrial content in blood-brain barrier endothelial cells during experimental autoimmune encephalomyelitis. Am J Pathol 6:1157–1168

    Google Scholar 

  7. Damle NK, Doyle LV, Bender JR, Bradley EC (1987) Interleukin 2-activated human lymphocytes exhibit enhanced adhesion to normal vascular endothelial cells and cause their lysis. J Neuroimmunol 138:1779–1785

    Google Scholar 

  8. Davson H, Welch K, Segal MB (1987) The physiology and pathophysiology of the cerebrospinal fluid. Churchill Livingstone, London, pp 523–582

    Google Scholar 

  9. Gonzalez-Scarano F, Grossman RI, Galetta S, Atlas SW, Silberberg DH (1987) Multiple sclerosis disease activity correlates with gadolinium enhanced magnetic resonance imaging. Ann Neurol 21:300–306

    Google Scholar 

  10. Greenwood J, Luthert PJ, Pratt OE, Lantos PL (1985) Maintenance of the integrity of the blood-brain barrier in the rat during an in situ saline-based perfusion. Neurosci Lett 56:223–227

    Google Scholar 

  11. Greenwood J, Luthert PJ, Pratt OE, Lantos PL (1988) Hyperosmolar opening of the blood-brain barrier in the energy-depleted rat brain. 1. Permeability studies. J Cereb Blood Flow Metab 8:9–15

    Google Scholar 

  12. Grossmann RI, Gonzalez-Scarano F, Atlas SW, Galetta S, Silberberg DH (1986) Multiple sclerosis: gadolinium enhancement in MR imaging. Radiology 161:721–725

    Google Scholar 

  13. 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 using gadolinium-DTPA and protein markers. Brain 113:365–378

    Google Scholar 

  14. Hawkins CP, MacKenzie F, Tofts PS, du Boulay EPGH, McDonald WI (1991) Patterns of blood-brain barrier breakdown in inflammatory demyelination. Brain 114:801–810

    Google Scholar 

  15. Kappos L, Stadt D, Roharbach E, Keil W (1988) Gadolinium-DTPA enhanced magnetic resonance imaging in the evaluation of different disease course and disease activity in MS (abstract). Neurology 38 [Suppl 1]:255

    Google Scholar 

  16. Kato S, Nakamura H (1987) Localization of adenosine triphosphatase activity of the endothelia in chronic relapsing experimental allergic encephalomyelitis. J Neuroimmunol 16:273–282

    Google Scholar 

  17. Kermode AG, Tofts PS, Thompson AJ, Macmanus DG, Rudge P, Kendall BE, Kingsley DPE, Moseley IF, du Boulay EPGH, McDonald WI (1990) Heterogeneity of blood-brain barrier changes in multiple sclerosis. Neurology 40:229–235

    Google Scholar 

  18. Kitz K, Lassmann H, Karcher D, Lowenthal A (1984) Blood-brain barrier in chronic relapsing experimental allergic encephalomyelitis: correlative study between cerebrospinal fluid protein concentrations and tracer leakage in the central nervous system. Acta Neuropathol (Berl) 63:41–50

    Google Scholar 

  19. Koopmans RA, Li DK, Oger JJF, Mayo J, Paty DW (1989) The lesion of multiple sclerosis: imaging of acute and chronic stages. Neurology 39:959–963

    Google Scholar 

  20. Kristensson K, Wisniewski HM (1977) Chronic relapsing experimental allergic encephalomyelitis. Studies in vascular permeability changes. Acta Neuropathol (Berl) 39:189–194

    Google Scholar 

  21. Lampert PW, Carpenter S (1965) Electron microscopic studies on the vascular permeability and the mechanisms of demyelination in experimental allergic encephalomyelitis. J Neuropathol Exp Neurol 24:11–24

    Google Scholar 

  22. Lassmann Hans (1983) Comparative neuropathology of chronic experimental allergic encephalomyelitis and multiple sclerosis. Springer, Berlin Heidelberg New York

    Google Scholar 

  23. Lossinsky AS, Badmajew V, Robson JA, Moretz RC, Wisniewski HM (1989) Sites of egress of inflammatory cells and horseradish peroxidase transport across the blood-brain barrier in a murine model of chronic relapsing experimental allergic encephalomyelitis. Acta Neuropathol 78:359–371

    Google Scholar 

  24. Luthert PJ, Greenwood J, Pratt OE, Lantos PL (1987) The effect of a metabolic inhibitor upon the properties of the cerebral vasculature during a whole-head saline perfusion of the rat. Q J Exp Phys 72:129–141

    Google Scholar 

  25. Male D, Pryce G (1989) Induction of Ia molecules on brain endothelium is related to susceptibility to experimental allergic encephalomyelitis. J Neuroimmunol 21:87–90

    Google Scholar 

  26. Miller DH, Rudge P, Johnson G, Kendall BE, MacManus DG, Moseley IF, Barnes D, McDonald WI (1988) serial gadolinium enhanced magnetic resonance imaging in multiple sclerosis. Brain 111:927–939

    Google Scholar 

  27. Nagy Z, Peters H, Huttner I (1981) Endothelial surface charge: blood-brain barrier opening to horseradish peroxidase induced by the polycation protamin sulfate. Acta Neuropathol (Berl) [Suppl VII]:7–9

  28. Shaklai M, Tavassoli M (1977) A modified technique to obtain uniform precipitation of lanthanum tracer in the extracellular space. J Histochem Cytochem 25:1013–1015

    Google Scholar 

  29. Willoughby EW, Grochowski E, Li DKB, Oger J, Kastrukoff LF, Paty DW (1989) Serial magnetic resonance scanning in multiple sclerosis: a second prospective study in relapsing patients. Ann Neurol 25:43–49

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Multiple Sclerosis Research Group, Institute of Neurology, National Hospital, Queen Square, WCIN 3BG, London, UK

    C. P. Hawkins, P. M. G. Munro, D. N. Landon & W. I. McDonald

Authors
  1. C. P. Hawkins
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P. M. G. Munro
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D. N. Landon
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. W. I. McDonald
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

Supported in part by Picker International. The Multiple Sclerosis NMR Research Group was established with a generous grant from the Multiple Sclerosis Society of Great Britain and Northern Ireland and additional support is provided by the Medical Research Council

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hawkins, C.P., Munro, P.M.G., Landon, D.N. et al. Metabolically dependent blood-brain barrier breakdown in chronic relapsing experimental allergic encephalomyelitis. Acta Neuropathol 83, 630–635 (1992). https://doi.org/10.1007/BF00299413

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00299413

Key words

Search

Navigation