Skip to main content

The Blood-Nerve Barrier: Structure and Functional Significance

  • Protocol
  • First Online:
The Blood-Brain and Other Neural Barriers

Part of the book series: Methods in Molecular Biology ((MIMB,volume 686))

Abstract

The blood–nerve barrier (BNB) defines the physiological space within which the axons, Schwann cells, and other associated cells of a peripheral nerve function. The BNB consists of the endoneurial microvessels within the nerve fascicle and the investing perineurium. The restricted permeability of these two barriers protects the endoneurial microenvironment from drastic concentration changes in the vascular and other extracellular spaces. It is postulated that endoneurial homeostatic mechanisms regulate the milieu intérieur of peripheral axons and associated Schwann cells. These mechanisms are discussed in relation to nerve development, Wallerian degeneration and nerve regeneration, and lead neuropathy. Finally, the putative factors responsible for the cellular and molecular control of BNB permeability are discussed. Given the dynamic nature of the regulation of the permeability of the perineurium and endoneurial capillaries, it is suggested that the term blood–nerve interface (BNI) better reflects the functional significance of these structures in the maintenance of homeostasis within the endoneurial microenvironment.

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

Access this chapter

Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 139.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 179.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Sunderland S (1978) Nerves and nerve injury. Churchill Livingstone, Edinburgh

    Google Scholar 

  2. Weerasuriya A, Rapoport SI, Taylor RE (1979) Modification of permeability of frog perineurium to (14C) sucrose by stretch and hypertonicity. Brain Res 173:503–512

    Article  PubMed  CAS  Google Scholar 

  3. Weerasuriya A, Rapoport SI, Taylor RE (1980) Ionic permeabilities of the frog perineurium. Brain Res 191, 405–415

    Article  PubMed  CAS  Google Scholar 

  4. Haller FR, Low FN (1971) The fine structure of the peripheral nerve root sheath in the subarachnoid space in the rat and other laboratory animals. Am J Anat 131:1–19

    Article  PubMed  CAS  Google Scholar 

  5. Shanthaveerappa TS, Bourne GH (1962) The ‘perineurial epithelium’, a metabolically active, continuous, protoplasmic cell barrier surrounding peripheral nerve fasciculi. J Anat 96:527–537

    PubMed  CAS  Google Scholar 

  6. Haller FR, Haller C, Low FN (1972) The fine structure of cellular layers and connective tissue space at spinal nerve root attachment in the rat. Am J Anat 133:109–123

    Article  PubMed  CAS  Google Scholar 

  7. Fraher JP (1999) The transitional zone and CNS regeneration. J Anat 194:161–182

    Article  PubMed  Google Scholar 

  8. Bell MA, Wedell AGM (1984) A morphometric study of intrafascicular vessels in mammalian sciatic nerve. Muscle Nerve 7:524–534

    Article  PubMed  CAS  Google Scholar 

  9. Olsson Y (1990) Microenvironment of the peripheral nervous system under normal and pathological conditions. Critical Rev Neurobiol 5:265–311

    CAS  Google Scholar 

  10. Olsson Y, Kristensson K (1971) Permeability of blood vessels and connective tissue sheaths in the peripheral nervous system to exogenous proteins. Acta Neuropathol 5:61–69

    PubMed  Google Scholar 

  11. Lundborg G (1988) Nerve injury and repair. Churchill Livingstone, Edinburgh

    Google Scholar 

  12. Peters A, Palay SL, DeF Webster H (1991) The fine structure of the nervous system. Oxford University Press, New York

    Google Scholar 

  13. Shanthaveerappa TS, Bourne GH (1966) Perineurial epithelium: a new concept of its role in the integrity of the peripheral nervous system. Science 154:1464–1467

    Article  PubMed  CAS  Google Scholar 

  14. Bunge MB, Wood PM, Tynan LB et al (1989) Perineurium originates from fibroblasts: demonstration in vitro with a retroviral marker. Science 243:229–231

    Article  PubMed  CAS  Google Scholar 

  15. Shinowara NL, Michel ME, Rapoport SI (1982) Morphological correlates of permeability in the frog perineurium: vesicles and transcellular channels. Cell Tissue Res 227: 11–22

    Article  PubMed  CAS  Google Scholar 

  16. Olsson Y (1984) Vascular permeability in the peripheral nervous system. In: Dyck PJ, Thomas PK, Lambert EH,Bunge R (eds) Peripheral neuropathy, 2nd edn. Saunders, Philadelphia

    Google Scholar 

  17. Ross MH, Reith EJ (1969) Perineurium: evidence for contractile elements. Science 165: 604–605

    Article  PubMed  CAS  Google Scholar 

  18. Burkel WE (1967) The histological fine structure of perineurium. Anat Rec 158:177–190

    Article  PubMed  CAS  Google Scholar 

  19. Olsson Y, Reese TS (1971) Permeability of vasa nervorum and perineurium in mouse sciatic nerve studied by fluorescence and electron microscopy. J Neuropathol Exp Neurol 30:105–119

    Article  PubMed  CAS  Google Scholar 

  20. Myers RR, Urakami H, Powell HC (1986) Reduced nerve blood flow in edematous neuropathies – a biochemical mechanism. Microvasc Res 32:145–151

    Article  PubMed  CAS  Google Scholar 

  21. Olsson Y (1966) Studies on vascular permeability in peripheral nerve I Acta Neuropathol 7: 1–15

    Article  PubMed  CAS  Google Scholar 

  22. Olsson Y (1968) Topographical differences in the vascular permeability of the peripheral nervous system. Acta Neuropathol 10:26–33

    Article  PubMed  CAS  Google Scholar 

  23. Kristensson K, Olsson Y (1971) The perineurium as a diffusion barrier to protein tracers; differences between mature and immature animals. Acta Neuropathol 17:127–138

    Article  PubMed  CAS  Google Scholar 

  24. Arvidson B (1979) A study of the perineurial diffusion barrier of a peripheral ganglion. Acta Neuropathol 46:139–44

    Article  PubMed  CAS  Google Scholar 

  25. Jacobs JM, Macfarlane RM, Cavanagh JB (1976) Vascular leakage in the dorsal root ganglia of the rat, studied with horseradish peroxidase. J Neurol Sci 29:95–107

    Article  PubMed  CAS  Google Scholar 

  26. Krnjevic K (1954) Some observations on perfused frog sciatic nerves. J Physiol 123: 338–356

    PubMed  CAS  Google Scholar 

  27. Rapoport SI (1976) Blood-brain barrier in physiology and medicine. Raven Press, New York

    Google Scholar 

  28. Soderfeldt B (1974) The perineurium as a diffusion barrier to protein tracers. Influence of histamine, serotonine and bradykinine. Acta Neuropathol 27:55–60

    Article  PubMed  CAS  Google Scholar 

  29. Boddingius J (1984) Ultrastructural and histophysiological studies on the blood-nerve barrier and perineurial barrier in leprosy neuropathy. Acta Neuropathol 64:282–296

    Article  PubMed  CAS  Google Scholar 

  30. Weerasuriya A (1990) Permeabilities of endoneurial capillaries and perineurium of rat sciatic nerve to 22Na during development. Physiologist 33:A-100

    Google Scholar 

  31. Weerasuriya A, Rapoport SI (1986) Endoneurial capillary permeability to (14C) sucrose in frog sciatic nerve. Brain Res 375:150–156

    Article  PubMed  CAS  Google Scholar 

  32. Weerasuriya A (1987) Permeability of endoneurial capillaries to K, Na, and Cl and its relation to peripheral nerve excitability. Brain Res 419:188–196

    Article  PubMed  CAS  Google Scholar 

  33. Weerasuriya A (1988) Patterns of change in endoneurial capillary permeability and vascular space during Wallerian degeneration. Brain Res 445:181–187

    Article  PubMed  CAS  Google Scholar 

  34. Weerasuriya A, Curran GL, Poduslo JF (1989) Blood-nerve transfer of albumin and its implications for the endoneurial microenvironment. Brain Res 494:114–121

    Article  PubMed  CAS  Google Scholar 

  35. Grotte G (1956) Passage of dextran molecules across the blood-lymph barrier. Acta Chir Scand Suppl 211:1–84

    PubMed  CAS  Google Scholar 

  36. Pappenheimer JR (1953) Passage of molecules through capillary walls. Physiol Rev 33:387–423

    PubMed  CAS  Google Scholar 

  37. Karnovsky MJ (1970) Morphology of capillaries with special reference to muscle capillaries. In: Crone C, Lassen NA (eds) Capillary permeability. Munksgaard, Copenhagen

    Google Scholar 

  38. Renkin EM (1977) Multiple pathways of capillary permeability. Circ Res 41:735–743

    PubMed  CAS  Google Scholar 

  39. Bundgaard M, Frokjaer-Jensen J (1982) Functional aspects of the ultrastructure of terminal blood vessels: a quantitative study on consecutive segments of the frog mesenteric microvasculature. Microvasc Res 23:1–30

    Article  PubMed  CAS  Google Scholar 

  40. Crone C, Levitt DG (1984) Capillary permeability to small solutes. In: Renkin EM, Michel CC (eds) Handbook of physiology. The cardiovascular system, vol 4. Microcirculation American Physiological Society, Bethesda

    Google Scholar 

  41. Rippe B, Haraldsson B (1987) How are macromolecules transported across the capillary wall? News Physiol Sci 2:135–138

    CAS  Google Scholar 

  42. Taylor AE, Granger DN (1984) Exchange of macromolecules across the microcirculation. In: Renkin EM, Michel CC (eds) Handbook of physiology, Sect 2, The cardiovascular system, vol 4. Microcirculation American Physiological Society, Bethesda

    Google Scholar 

  43. Smith ME, Jones TA, Hilton D (1998) Vascular endothelial cadherin is expressed by perineurial cells of peripheral nerve. Histopathology 32:411–413

    Article  PubMed  CAS  Google Scholar 

  44. Tserentsoodol N, Shin BC, Koyama H, et al (1999) Immunolocalization of tight junction proteins, occludin and ZO-1, and GLUT1 in the cells of the blood-nerve barrier. Arch Histol Cytol 62:459–469

    Article  PubMed  CAS  Google Scholar 

  45. Nesbitt JA, Acland RD (1980) Histopathological changes following removal of the perineurium. J Neurosurg 53:233–238

    Article  PubMed  CAS  Google Scholar 

  46. Nukada H, Powell HC, Myers RR (1992) Perineurial window: demyelination in nonherniated endoneurium with reduced nerve blood flow. J Neuropathol Exp Neurol 51: 523–530

    Article  PubMed  CAS  Google Scholar 

  47. Spencer PS, Weinberg HJ, Raines CS (1975) The perineurial window – a new model of focal demyelination and remyelination. Brain Res 96:323–329

    Article  PubMed  CAS  Google Scholar 

  48. Terho PM, Vuorinen VS, Roytta M (2002) The endoneurial response to microsurgically removed epi- and perineurium. J Peripheral Nerv Syst 7:155–162

    Article  Google Scholar 

  49. Rechthand E, Smith QR, Rapoport SI (1985) Facilitated transport of glucose from blood into peripheral nerve. J Neurochem 45:957–964

    Article  PubMed  CAS  Google Scholar 

  50. Froehner SC, Davies A, Baldwin SA et al (1988) The blood-nerve barrier is rich in glucose transporter. J Neurocytol 17:173–178

    Article  PubMed  CAS  Google Scholar 

  51. Gerhart DZ, Drewes LR (1990) Glucose transporters at the blood-nerve barrier are associated with perineurial cells and endoneurial microvessels. Brain Res 508:46–50

    Article  PubMed  CAS  Google Scholar 

  52. Magnani P, Cherian PV, Gould GW et al (1996) Glucose transporters in rat peripheral nerve: paranodal expression of GLUT1 and GLUT3. Metabolism 45:1466–1473

    Article  PubMed  CAS  Google Scholar 

  53. Rechthand E, Smith QR, Rapoport SI (1988) A compartmental analysis of solute transfer and exchange across blood-nerve barrier. Am J Physiol 255:317–325

    Google Scholar 

  54. Smith QR, Allen DD (2003) In situ brain perfusion technique. Methods Mol Med 89: 209–213

    PubMed  Google Scholar 

  55. Rydevik BL, Kwan MK, Myers RR, et al (1990) Effects of acute stretching on rabbit tibial nerve: an in vitro mechanical and histological study. J Orthop Res 8:694–701

    Article  PubMed  CAS  Google Scholar 

  56. Weiss P, Wang H, Taylor AC et al (1945) Proximo-distal fluid convection in the endoneurial spaces of peripheral nerves, demonstrated by colored and radioactive (isotope) tracers. Am J Physiol 143:521–540

    Google Scholar 

  57. Mellick RS, Cavanagh JB (1967) Longitudinal movement of radio-iodinated albumin within extravascular spaces of peripheral nerves following three systems of trauma. J Neurol Neurosurg Psychiat 30:458–463

    Article  PubMed  CAS  Google Scholar 

  58. Low PA (1985) Endoneurial potassium is increased and enhances spontaneous activity in regenerating mammalian nerve fibers. Implications for neuropathic positive symptom. Muscle Nerve 8:27–33

    Article  PubMed  CAS  Google Scholar 

  59. McCabe JS, Low FN (1969) The subarachnoid angle: an area of transition in peripheral nerve. Anat Rec 164:15–33

    Article  PubMed  CAS  Google Scholar 

  60. Waksman BH (1961) Experimental study of diphtheritic polyneuritis in the rabbit and guinea pig. III. The blood-nerve barrier in the rabbit. J Neuropathol Exp Neurol 20: 35–77

    Article  PubMed  CAS  Google Scholar 

  61. Powell HC, Myers RR (1989) The blood-nerve barrier and the pathological significance of nerve edema. In: Neuwelt EA (ed) Implications of the blood-brain barrier and its manipulation, vol 1. Plenum Press, New York

    Google Scholar 

  62. Myers RR, Rydevik BL, Heckman HM et al (1988) Proximo-distal gradient in endoneurial fluid pressure. Exp Neurol 102:368–370

    Article  PubMed  CAS  Google Scholar 

  63. Low FN (1976) The perineurium and connective tissue of peripheral nerve. In: Landon DN (ed) The peripheral nerve. Chapman and Hall, London

    Google Scholar 

  64. Poduslo JF, Curran GL, Dyck PJ (1988) Increase in albumin, IgG and IgM blood-nerve barrier indices in human diabetic neuropathy. Proc Natl Acad Sci 88:4879–4883

    Article  Google Scholar 

  65. Weerasuriya A (2005) Blood-nerve interface and endoneurial homeostasis. In: Dyck PJ, Thomas PK (eds) Peripheral neuropathy, 4th ed. Elsevier, New York

    Google Scholar 

  66. Kandel ER, Schwartz JH, Jessell TM (2000) Principles of neural science. 4th edn. McGraw-Hill, New York

    Google Scholar 

  67. Landis EM, Pappenheimer JR (1963) Exchange of substances through the capillary wall. In: Hamilton WF, Dow P (eds) Handbook of physiology, Circulation, Sect 2, vol II. American Physiological Society, Washington DC

    Google Scholar 

  68. Mizisin AP, Kalichman MW (1993) Permeability and surface area of the blood-nerve barrier in galactose intoxication. Brain Res 618:109–114

    Article  PubMed  CAS  Google Scholar 

  69. Crowley NR, Nelson SL, Weerasuriya A. et al (1996) Endoneurial hydrostatic pressure in rat sciatic nerve during development. Soc Neurosci Abstr 22:772

    Google Scholar 

  70. Rechthand E, Smith QR, Rapoport SI (1987) Transfer of nonelectrolytes from blood into peripheral nerve endoneurium. Am J Physiol 252:H1175–H1182

    PubMed  CAS  Google Scholar 

  71. Schmelzer JD, Low PA (1988) The effects of hyperbaric oxygenation and hypoxia on the blood-nerve barrier. Brain Res 473: 321–326

    Article  PubMed  CAS  Google Scholar 

  72. Low PA, Tuck RR (1984) Effects of changes in blood pressure, respiratory acidosis and hypoxia on blood flow in the sciatic nerve of the rat. J Physiol 347:513–524

    PubMed  CAS  Google Scholar 

  73. Rundquist I, Smith QR, Michael ME et al (1985) Sciatic nerve blood flow measured by laser Doppler flowmetry and (14C) iodoantipyrine. Am J Physiol 248:H311-H317

    PubMed  CAS  Google Scholar 

  74. Low PA, Marchand G, Knox F et al (1977) Measurement of endoneurial fluid pressure with polyethylene matrix capsule. Brain Res 122:373–377

    Article  PubMed  CAS  Google Scholar 

  75. Myers RR, Powell HC, Costello ML et al (1978) Endoneurial fluid pressure: direct measurement with micropipettes. Brain Res 148:510–515

    Article  PubMed  CAS  Google Scholar 

  76. Weerasuriya A, Coath G, Crowley N (1996) Endoneurial Na concentration and hydrostatic pressure in galactose neuropathy. FASEB J 10:A764

    Google Scholar 

  77. Weerasuriya A, Curran GL, Poduslo JF (1990) Developmental changes in blood-nerve transfer of albumin and endoneurial albumin content in rat sciatic nerve. Brain Res 521:40–46

    Article  PubMed  CAS  Google Scholar 

  78. Stoll G, Jander S, Myers RR (2002) Degeneration and regeneration in the peripheral nervous system: from August Waller’s observation on neuroinflammation. J Peripher Nerv Syst 7:13–27

    Article  PubMed  Google Scholar 

  79. Tsao JW, George EB, Griffin JW (1999) Temperature modulation reveals three distinct stages of Wallerian degeneration. J Neurosci 19:4718–4726

    PubMed  CAS  Google Scholar 

  80. Weerasuriya A, Hockman CH (1992) Perineurial permeability to sodium during Wallerian degeneration in rat sciatic nerve. Brain Res 587:327–333

    Article  Google Scholar 

  81. Latker CH, Wadhwani KC., Balbo A et al (1991) Blood-nerve barrier in the frog during Wallerian degeneration: are axons necessary for maintenance of barrier function? J Comp Neurol 309:650–664

    Article  Google Scholar 

  82. Williams PL, Hall SM (1971) Chronic Wallerian degeneration – an in vivo and ultrastructural study. J Anat 109:487–503

    PubMed  CAS  Google Scholar 

  83. Stoll G, Trapp BD, Griffin JW (1989) Macrophage function during Wallerian degeneration of rat optic nerve: clearance of degenerating myelin and Ia expression J Neurosci 9:2327–2335

    PubMed  CAS  Google Scholar 

  84. Weerasuriya A, Nelson SL, Crowley NR (1998) Evidence for endoneurial fluid flow from endoneurial hydrostatic pressure measurements in transected and crushed rat sciatic nerves. Soc Neurosci Abstr 24:267

    Google Scholar 

  85. Low PA, Dyck PJ (1977) Increased endoneurial fluid pressure in experimental lead neuropathy. Nature 269:427–428

    Article  PubMed  CAS  Google Scholar 

  86. Myers RR, Powell HC, Shapiro HM, et al (1980) Changes in endoneurial fluid pressure, permeability and peripheral nerve ultrastructure in experimental lead neuropathy. Ann Neurol 8:392–401

    Article  PubMed  CAS  Google Scholar 

  87. Powell HC, Myers RR, Lampert PW (1982) Changes in Schwann cells and vessels in lead neuropathy. Am J Pathol 109:193–205

    PubMed  CAS  Google Scholar 

  88. Windebank AJ, McCall JT, Hunder HG et al (1980) The endoneurial content of lead related to the onset and severity of segmental demyelination. J Neuropathol Exp Neurol 39: 692–699.

    Article  PubMed  CAS  Google Scholar 

  89. Ohi T, Poduslo JF, Curran GL et al (1985) Quantitative methods for detection of blood-nerve barrier alterations in experimental animal models of neuropathy. Exp Neurol 90:365–372

    Article  PubMed  CAS  Google Scholar 

  90. Weerasuriya A, Curran GL, Poduslo JF (1990) Physiological changes in the sciatic nerve endoneurium of lead intoxicated rats: a model of endoneurial homeostasis. Brain Res 517:1–6

    Article  PubMed  CAS  Google Scholar 

  91. Abbott NJ (2002) Astrocyte-endothelial interactions and blood-brain barrier permeability. J Anat 200:629–638

    Article  PubMed  CAS  Google Scholar 

  92. Lo EH, Broderick JP, Moskowitz MA (2004) tPA and proteolysis in the neurovascular unit. Stroke 35:354–356

    Article  PubMed  Google Scholar 

  93. Wadhwani KC, Latker CH, Balbo A et al (1989) Perineurial permeability and endoneurial edema during Wallerian degeneration of the frog peripheral nerve. Brain Res 493:231–239

    Article  PubMed  CAS  Google Scholar 

  94. Weerasuriya A, Rapoport SI, Taylor RE (1980) Perineurial permeability increases during Wallerian degeneration. Brain Res 192: 581–585

    Article  PubMed  CAS  Google Scholar 

  95. Griffin JW (2001) Vasculitic neuropathies. Rheum Dis Clin North Am 27:751–760

    Article  PubMed  CAS  Google Scholar 

  96. Polydefkis M, Griffin JW, McArthur J (2003) New insights into diabetic polyneuropathy. JAMA 290:1371–1376

    Article  PubMed  CAS  Google Scholar 

  97. Powell HC, Myers RR (2004) Impact of inflammatory disease on the nerve microenvironment. J Neurol Sci 220:131–132

    Article  PubMed  Google Scholar 

  98. Zhou L, Griffin JW (2003) Demyelinating polyneuropathies. Curr Opin Neurol 16: 307–313

    Article  PubMed  Google Scholar 

  99. Abbott NJ (2000) Inflammatory mediators and modulation of blood-brain barrier permeability. Cell Mol Neurobiol 20:131–147

    Article  PubMed  CAS  Google Scholar 

  100. Anderson CM, Nedergaard M (2003) Astrocyte-mediated control of cerebral microcirculation. Trends Neurosci 26: 340–345

    Article  PubMed  CAS  Google Scholar 

  101. Gloor SM, Wachtel M, Bolliger MF et al (2001) Molecular and cellular permeability control at the blood-brain barrier. Brain Res Brain Res Rev 36:258–264

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work is partially supported by RO1–NS30197 and RO1-DI2078374 (NIH), IBN-9420525 (NSF), Juvenile Diabetes Research Foundation and MedCen Foundation, Macon, GA (No. 23750). The invaluable assistance of Mr. Daniel Mizisin and Mr. John Knight in the preparation of figures and discussions with Dr. Quentin Smith are gratefully acknowledged.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Ananda Weerasuriya .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer Science+Business Media, LLC

About this protocol

Cite this protocol

Weerasuriya, A., Mizisin, A.P. (2011). The Blood-Nerve Barrier: Structure and Functional Significance. In: Nag, S. (eds) The Blood-Brain and Other Neural Barriers. Methods in Molecular Biology, vol 686. Humana Press. https://doi.org/10.1007/978-1-60761-938-3_6

Download citation

  • DOI: https://doi.org/10.1007/978-1-60761-938-3_6

  • Published:

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-60761-937-6

  • Online ISBN: 978-1-60761-938-3

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics