Medical Physiology, 3rd Edition

The Blood-Brain Barrier

The blood-brain barrier prevents some blood constituents from entering the brain extracellular space

The unique protective mechanism now called the BBB was first demonstrated by Ehrlich in 1885. He injected aniline dyes intravenously and discovered that the soft tissues of the body, except for the brain, were uniformly stained. Aniline dyes, such as trypan blue, extensively bind to serum albumin, and the dye-albumin complex passes across capillaries in most areas of the body, but not the brain. This ability to exclude certain substances from crossing CNS blood vessels into the brain tissue is due to the blood-brain barrier. We now recognize that a BBB is present in all vertebrates and many invertebrates as well.

The need for a BBB can be understood by considering that blood is not a suitable environment for neurons. Blood is a complex medium that contains a large variety of solutes, some of which can vary greatly in concentration, depending on factors such as diet, metabolism, illness, and age. For example, the concentration of many amino acids increases significantly after a protein-rich meal. Some of these amino acids act as neurotransmitters within the brain, and if these molecules could move freely from the blood into the neuronal microenvironment, they would nonselectively activate receptors and disturb normal neurotransmission. Similarly, strenuous exercise can increase plasma concentrations of K+ and H+ substantially. If these ionic changes were communicated directly to the microenvironment of neurons, they could disrupt ongoing neural activity. Running a foot race might temporarily lower your IQ. Increases in [K+]o would depolarize neurons and thus increase their likelihood of firing and releasing transmitter. H+ can nonspecifically modulate neuronal excitability and influence the action of certain neurotransmitters. A broad range of blood constituents—including hormones, other ions, and inflammatory mediators such as cytokines—can influence the behavior of neurons or glial cells, which can express receptors for these molecules. For the brain to function efficiently, it must be spared such influences.

The choroid plexus and several restricted areas of the brain lack a BBB; that is, they are supplied by leaky capillaries. Intra-arterially injected dyes can pass into the BECS at these sites through gaps between endothelial cells. The BECF in the vicinity of these leaky capillaries is more similar to blood plasma than to normal BECF. The small brain areas that lack a BBB are called the circumventricular organs because they surround the ventricular system; these areas include the area postrema, posterior pituitary, median eminence, organum vasculosum laminae terminalis, subfornical organ, subcommissural organ, and pineal gland (Fig. 11-7). The ependymal cells that overlie the leaky capillaries in some of these regions (e.g., the choroid plexus) are linked together by tight junctions that form a barrier between the local BECF and the CSF, which must be insulated from the variability of blood composition. Whereas dyes with molecular weights up to 5000 can normally pass from CSF across the ependymal cell layer into the BECF, they do not pass across the specialized ependymal layer at the median eminence, area postrema, and infundibular recess. At these points, the localized BECF-CSF barrier is similar to the one in the choroid plexus. These specialized ependymal cells often have long processes that extend to capillaries within the portal circulation of the pituitary. Although the function of these cells is not known, it has been suggested that they may form a special route for neurohumoral signaling; molecules secreted by hypothalamic cells into the third ventricle could be taken up by these cells and transmitted to the general circulation or to cells in the pituitary.

image

FIGURE 11-7 Leaky regions of the BBB: the circumventricular organs. The capillaries of the brain are leaky in several areas: the area postrema, the posterior pituitary, the subfornical organ, the median eminence, the pineal gland, and the organum vasculosum laminae terminalis (OVLT). In these regions, the neurons are directly exposed to the solutes of the blood plasma. A midline sagittal section is shown.

Neurons within the circumventricular organs are directly exposed to blood solutes and macromolecules; this arrangement is believed to be part of a neuroendocrine control system for maintaining such parameters as osmolality (see p. 844) and appropriate hormone levels, among other things. Humoral signals are integrated by connections of circumventricular organ neurons to endocrine, autonomic, and behavioral centers within the CNS. In the median eminence, neurons discharge “releasing hormones,” which diffuse into leaky capillaries for carriage through the pituitary portal system to the anterior pituitary (see p. 978). The lack of a BBB in the posterior pituitary is necessary to allow hormones that are released there to enter the general circulation (see p. 979). In the organum vasculosum laminae terminalis, leakiness is important in the action of cytokines from the periphery, which act as signals to temperature control centers that are involved in fever (see p. 1202).

Continuous tight junctions link brain capillary endothelial cells

The BBB should be thought of as a physical barrier to diffusion from blood to BECF and as a selective set of regulatory transport mechanisms that determine how certain organic solutes move between the blood and brain. Thus, the BBB contributes to stabilization and protection of the neuronal microenvironment by facilitating the entry of needed substances, removing waste metabolites, and excluding toxic or disruptive substances.

The structure of brain capillaries differs from that of capillaries in other organs (Fig. 11-8A). Capillaries in other organs generally have small, simple openings—or clefts—between their endothelial cells. In some of these other organs, windows, or fenestrae, provide a pathway that bypasses the cytoplasm of capillary endothelial cells. Thus, in most capillaries outside the CNS, solutes can easily diffuse through the clefts and fenestrae. The physical barrier to solute diffusion in brain capillaries (see Fig. 11-8B) is provided by the capillary endothelial cells, which are fused to each other by continuous tight junctions (or zonula occludens; see pp. 43–44). The tight junctions prevent water-soluble ions and molecules from passing from the blood into the brain through the paracellular route. Not surprisingly, the electrical resistance of the cerebral capillaries is 100 to 200 times higher than that of most other systemic capillaries.

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FIGURE 11-8 BBB function of brain capillaries. A, Capillaries from most other organs often have interendothelial clefts or fenestrae, which makes them relatively leaky. B, Brain capillaries are not leaky and have reduced transcytosis. C, Continuous tight junctions connect the endothelial cells in the brain, making the capillaries relatively tight. GLUT1, glucose transporter 1.

Elsewhere in the systemic circulation, molecules may traverse the endothelial cell by the process of transcytosis (see p. 467). In cerebral capillaries, transcytosis is uncommon, and brain endothelial cells have fewer endocytic vesicles than do systemic capillaries. However, brain endothelial cells have many more mitochondria than systemic endothelial cells do, which may reflect the high metabolic demands imposed on brain endothelial cells by active transport.

Other interesting features of brain capillaries are the thick basement membrane that underlies the endothelial cells, the presence of occasional pericytes within the basement membrane sheath, and the astrocytic endfeet (or processes) that provide a nearly continuous covering of the capillaries and other blood vessels. Astrocytes may play a crucial role in forming tight junctions between endothelial cells; experiments have shown that these glial cells can induce the formation of tight junctions between endothelial cells derived from capillaries outside the CNS. The close apposition of the astrocyte endfoot to the capillary also could facilitate transport of substances between these cells and blood.

Uncharged and lipid-soluble molecules more readily pass through the blood-brain barrier

The capacity of the brain capillaries to exclude large molecules is strongly related to the molecular mass of the molecule and its hydrated diameter (Table 11-2). With a mass of 61 kDa, prealbumin is 14 times as concentrated in blood as in CSF (essentially equivalent to BECF for purposes of this comparison), whereas fibrinogen, which has a molecular mass of 340 kDa, is ~5000 times more concentrated in blood than in CSF. Diffusion of a solute is also generally limited by ionization at physiological pH, by low lipid solubility, and by binding to plasma proteins. For example, gases such as CO2 and O2 and drugs such as ethanol, caffeine, nicotine, heroin, and methadone readily cross the BBB. However, ions such as K+ or Mg2+ and protein-bound metabolites such as bilirubin have restricted access to the brain. Finally, the BBB is permeable to water mainly because of the presence of AQP4 in the astrocytic endfeet (see Fig. 11-8A). Thus, water moves across the BBB in response to changes in plasma osmolality. When dehydration raises the osmolality of blood plasma (see Box 11-3), the increased osmolality of the CSF and BECF can affect the behavior of brain cells.

TABLE 11-2

Comparison of Proteins in Blood Plasma and CSF

PROTEIN

MOLECULAR WEIGHT (kDa)

HYDRODYNAMIC RADIUS (nM)

PLASMA/CSF RATIO*

Prealbumin

61

3.3

14

Albumin

69

3.6

240

Transferrin

81

3.7

140

Ceruloplasmin

152

4.7

370

IgG

150

5.3

800

IgA

150

5.7

1350

α2-macroglobulin

798

9.4

1100

Fibrinogen

340

11.0

4940

IgM

800

12.1

1170

β-lipoprotein

2240

12.4

6210

*The greater the plasma/CSF ratio, the more the BBB excludes the protein from the CSF.

Ig, immunoglobulin.

Cerebral capillaries also express enzymes that can affect the movement of substances from blood to brain and vice versa. Peptidases, acid hydrolases, monoamine oxidase, and other enzymes are present in CNS endothelial cells and can degrade a range of biologically active molecules, including enkephalins, substance P, proteins, and norepinephrine. Orally administered dopamine is not an effective treatment of Parkinson disease (see p. 313), a condition in which CNS dopamine is depleted, because dopamine is rapidly broken down by monoamine oxidase in the capillaries. Fortunately, the dopamine precursor compound L-DOPA is effective for this condition. Neutral amino-acid transporters in capillary endothelial cells move L-DOPA to the BECF, where presynaptic terminals take up the L-DOPA and convert it to dopamine in a reaction that is catalyzed by DOPA decarboxylase.

Transport by capillary endothelial cells contributes to the blood-brain barrier

Two classes of substances can pass readily between blood and brain. The first consists of the small, highly lipid-soluble molecules discussed in the preceding section. The second group consists of water-soluble compounds—either critical nutrients entering or metabolites exiting the brain—that traverse the BBB by specific transporters. Examples include glucose, several amino acids and neurotransmitters, nucleic acid precursors, and several organic acids. Two major transporter groups provide these functions: the SLC superfamily (see pp. 111–114) and ABC transporters (see pp. 119–120). imageN11-3 As is the case for other epithelial cells, capillary endothelial cells selectively express these and other membrane proteins on either the luminal or basal surface.

N11-3

System L Amino-Acid Transporters in Brain Capillary Endothelial Cells

Contributed by Bruce Ransom

Large uncharged amino acids (i.e., phenylalanine, tyrosine, and leucine) are selectively transported into the brain by system L. As outlined in Table 36-1B, the system L protein is a heterodimer of SLC7A8 and SLC3A2. It has broad substrate specificity and transports across the BBB several important drugs that act on the brain, including L-DOPA (to treat Parkinson disease), baclofen (to reduce spasticity), and gabapentin (to treat chronic pain and epilepsy).

Although the choroid plexuses secrete most of the CSF, brain endothelial cells produce some interstitial fluid with a composition similar to that of CSF. Transporters such as those shown in Figure 11-8C are responsible for this CSF-like secretion as well as for the local control of [K+] and pH in the BECF.