Electron microscope studies have shown that capillaries in the brain have a continuous capillary endothelium with tight junctions and are therefore unlike the more permeable capillaries found elsewhere in the body. This effectively excludes the passage of many materials including proteins and molecules with molecular weights as low as 2000. The existence of the barrier was first demonstrated by Paul Ehrlich and later by Goldman, who in 1909 injected large amounts of the dye trypan blue into the vascular circulation and observed that all tissues became intensely stained while the brain remained "snow white." We now know that trypan blue was excluded from the brain because it rapidly complexed with albumen in the plasma and could not cross cerebral capillaries in this form. Many materials do, however, cross the barrier from plasma to brain. Nevertheless, it's a "selective" barrier where some materials are excluded or cross with difficulty and others pass quite freely. Because of the heavy dependence of the brain on a steady supply of oxygen for cellular respiration and glucose for energy metabolism, it is not surprising to find that they pass freely into the brain with little hindrance. Similarly, metabolic wastes and carbon dioxide readily pass across the barrier from brain to plasma. On the other hand, free fatty acids, an easily accessible alternate energy source for most other cells of the body including muscle, are virtually excluded from the brain. A summary of the permeability of the blood-brain barrier to several different metabolic substances is illustrated in Fig. -1
|Diffusion Across the Barrier|
O2, CO2, N2O, Kr, and Xe are gases which readily diffuse across the barrier. The latter three have been used to calculate cerebral blood flow. Water also readily diffuses into and out of the brain. Its net movement is dictated solely by the osmolality of the plasma. Thus an increase in the plasma osmolality from its normal value of 290 mosmol/L can draw water from the brain by osmosis, and actually shrink its volume. This phenomenon has been employed clinically to reduce intracranial pressure by using plasma expanders such as mannitol to increase plasma osmolality. Mannitol does not cross the blood-brain barrier.
Lipid solubility is an important factor in diffusion across the barrier. Generally the higher the lipid solubility of a substance, the more readily it diffuses. Thus alcohols like ethanol move freely into the brain. Lipid-soluble thiobarbital equilibrates more rapidly between plasma and brain than the slightly less soluble barbital does. Salicylic acid is less soluble yet and thus requires even more time to equilibrate.
|Facilitated Transport across the Barrier|
Carrier systems appear to be involved in the transport of several materials across the barrier. Glucose, ions, and certain amino acids utilize this type of system. The carrier system for glucose is stereospecific as n-glucose, but not Lglucose, is readily transported into the brain. Lactic, pyruvic, and acetic acids also utilize such carriers.
While proteins are virtually excluded from the brain, certain amino acids pass readily into it. Included are the essential amino acids and those which are precursors for the production of neurotransmitters. The latter include tyrosine (required for norepinephrine and dopamine synthesis) and tryptophan (for serotonin synthesis). Similarly, neuroactive peptides whose amino acid sequences have been clearly identified such as substance P, methionine enkephalin and leucine enkephalin, ,B-endorphin, ACTH, angiotensin II, oxytocin, vasopressin, somatostatin, thyrotropin-releasing factor, and luteinizing hormone-releasing factor rely on a steady transport of these amino acids from plasma to brain for their continued synthesis.
Ions cross the barrier into brain but do so much more slowly than into other body tissues. An intravenous K + administration exchanges much more quickly with muscle tissue that it does with brain. Ca2+ and Mg2+ transport is equally slow, while N a + is somewhat faster. H+ ion transport into the brain is very slow.
Certain areas of the brain apparently contain no blood-brain barrier. These include the neurohypophysis, median eminence of the hypothalamus, the area postrema, and the pineal gland. Because many circulating hormones control their own release through negative feedback to the hypothalamus, the importance of barrier lack in this area is readily apparent. If such hormones are to influence the hypothalamic output of releasing or inhibiting factors to the anterior pituitary via the hypothalamohypophyseal portal system, they must not be barred from the hypothalamus by a barrier system. Similarly, osmoreceptors of the hypothalamus must be able to constantly and easily detect changes in the osmolality of the plasma if the release of antidiuretic hormone (ADH) is to proceed properly.