Serum proteins bypass the blood-brain fluid barriers for extracellular entry to the central nervous system

Exp Neurol. 1993 Apr;120(2):245-63. doi: 10.1006/exnr.1993.1059.


Extracellular pathways circumventing the mammalian blood-brain fluid barriers (e.g., blood-brain and blood-CSF barriers) have been investigated in the rat by immunohistochemical localization of the endogenous serum proteins albumin, IgG, complement C-9, and IgM and by the exogenous tracer protein horseradish peroxidase (HRP). A demonstrable extracellular pathway into the central nervous system (CNS) is evident at the level of the subarachnoid space/pial surface. Immunoreaction products for the serum proteins and reaction product of intravenously administered HRP are identified over the entire pial surface, in the Virchow-Robin spaces and subpial cortical grey matter, and within phagocytes occupying the subarachnoid space/pial surface and perivascular clefts throughout the CNS. From specific circumventricular organs (e.g., median eminence, area postrema, subfornical organ), well known to lie outside the blood-brain barrier (BBB), each of the blood-borne proteins readily enters adjacent white and grey matter and the ventricular system for subsequent rostrocaudal labeling of the ependymal cell lining. Similar immunohistochemical and blood-borne HRP results are obtained in the CNS of the neonatal rat. Peroxidase delivered into the aorta of postmortem adult rats confirms the presence of a BBB in brain sites containing blood vessels impermeable to blood-borne HRP and the absence of a BBB in sites revealed as leaky to blood-borne HRP in the live rat. The results suggest blood-borne macromolecules, including those of the immune and complement systems, have potential widespread, extracellular distribution within the CNS and cerebrospinal fluid from sites deficient in a BBB (e.g., subarachnoid space/pial surface, circumventricular organs). These observations may have important clinical implications regarding experimental and pathologic autoimmune dysfunction within the CNS and impact on the interpretation of potential transcytosis of blood-borne peptides and proteins through the cerebral endothelium in vivo. A summary diagram of suspected extracellular and intracellular pathways circumventing the blood-brain fluid barriers is provided.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Animals, Newborn
  • Artifacts
  • Blood Proteins / metabolism*
  • Blood-Brain Barrier*
  • Brain / cytology
  • Brain / metabolism*
  • Brain / ultrastructure
  • Cerebrovascular Circulation
  • Complement C9 / analysis
  • Extracellular Space / metabolism
  • Female
  • Horseradish Peroxidase / analysis
  • Horseradish Peroxidase / blood
  • Humans
  • Immunoglobulin G / analysis
  • Immunoglobulin M / analysis
  • Immunohistochemistry
  • Male
  • Microscopy, Electron
  • Models, Cardiovascular
  • Models, Neurological
  • Neurons / cytology
  • Neurons / physiology
  • Rats
  • Rats, Inbred WF
  • Rats, Wistar
  • Serum Albumin / analysis


  • Blood Proteins
  • Complement C9
  • Immunoglobulin G
  • Immunoglobulin M
  • Serum Albumin
  • Horseradish Peroxidase