Box EThe Blood-Brain Barrier

The interface between the walls of capillaries and the surrounding tissue is important throughout the body, as it keeps vascular and extravascular concentrations of ions and molecules at appropriate levels in these two compartments. In the brain, this interface is especially significant and has been accorded an alliterative name, “the blood-brain barrier.” The special properties of the blood-brain barrier were first observed by the nineteenth-century bacteriologist Paul Ehrlich, who noted that intravenously injected dyes leaked out of capillaries in most regions of the body to stain the surrounding tissues; the brain, however, remained unstained. Ehrlich wrongly concluded that the brain had a low affinity for the dyes; his student, Edwin Goldmann, showed that such dyes do not traverse the specialized walls of brain capillaries.

The restriction of large molecules like Ehrlich's dyes (and many smaller molecules) to the vascular space is the result of tight junctions between neighboring capillary endothelial cells in the brain. Such junctions are not found in capillaries elsewhere in the body, where the spaces between adjacent endothelial cells allow much more ionic and molecular traffic. The structure of tight junctions was first demonstrated in the 1960s by Tom Reese, Morris Karnovsky, and Milton Brightman. Using electron microscopy after the injection of electron-dense intravascular agents such as lanthanum salts, they showed that the close apposition of the endothelial cell membranes prevented such ions from passing. Substances that traverse the walls of brain capillaries must move through the endothelial cell membranes. Accordingly, molecular entry into the brain should be determined by an agent's solubility in lipids, the major constituent of cell membranes. Nevertheless, many ions and molecules not readily soluble in lipids do move quite readily from the vascular space into brain tissue. A molecule like glucose, the primary source of metabolic energy for neurons and glial cells, is an obvious example. This paradox is explained by the presence of specific transporters for glucose and other critical molecules and ions.

In addition to tight junctions, astrocytic “end feet” (the terminal regions of astrocytic processes) surround the outside of capillary endothelial cells. The reason for this endothelial—glial allegiance is unclear, but may reflect an influence of astrocytes on the formation and maintenance of the blood-brain barrier.

The brain, more than any other organ, must be carefully shielded from abnormal variations in its ionic milieu, as well as from the potentially toxic molecules that find their way into the vascular space by ingestion, infection, or other means. The blood-brain barrier is thus important for protection and homeostasis. It also presents a significant problem for the delivery of drugs to the brain. Large (or lipid-insoluble) molecules can be introduced to the brain, but only by transiently disrupting the blood-brain barrier with hyperosmotic agents like mannitol.

Image ch1fbe1.jpg

The cellular basis of the blood-brain barrier. (A) Diagram of a brain capillary in cross section and reconstructed views, showing endothelial tight junctions and the investment of the capillary by astrocytic end feet. (B) Electron micrograph of boxed area in (A), showing the appearance of tight junctions between neighboring endothelial cells (arrows). (A after Goldstein, Goldstein and Betz, 1986; B from Peters et al., 1991.)


  1. Brightman M. W. , Reese T. S. Junctions between intimately opposed cell membranes in the vertebrate brain. J. Cell Biol. (1969);40:648–677. [PMC free article: PMC2107650] [PubMed: 5765759]
  2. Schmidley, J. W. and E. F. Maas (1990) Cerebrospinal fluid, blood-brain barrier and brain edema. In Neurobiology of Disease, A. L. Pearlman and R.C. Collins (eds.). New York: Oxford University Press, Chapter 19, pp. 380–398.
  3. Reese T. S. , Karnovsky M. J. Fine structural localization of a blood—brain barrier to exogenous peroxidase. J. Cell Biol. (1967);34:207–217. [PMC free article: PMC2107213] [PubMed: 6033532]

From: The Blood Supply of the Brain and Spinal Cord

Cover of Neuroscience
Neuroscience. 2nd edition.
Purves D, Augustine GJ, Fitzpatrick D, et al., editors.
Sunderland (MA): Sinauer Associates; 2001.
Copyright © 2001, Sinauer Associates, Inc.

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