The blood–brain barrier develops early in the embryo through an interaction between glial astrocytes and capillary endothelial cells. The barrier is created largely by the elaborate tight junctions between the endothelial cells, which form continuous-type capillaries. Studies with the TEM using electron-opaque tracers show complex tight junctions between the endothelial cells. Morphologically, these junctions more closely resemble epithelial tight junctions than tight junctions present between other endothelial cells. In addition, TEM studies reveal a close association of astrocytes and their end foot processes with the endothelial basal lamina (Fig. 12.32). The tight junctions eliminate gaps between endothelial cells and prevent simple diffusion of solutes and fluid into the neural tissue. Evidence suggests that the integrity of blood–brain barrier tight junctions depends on normal functioning of the associated astrocytes. In several brain diseases, the blood–brain barrier loses effectiveness. Examination of brain tissue in these conditions by TEM reveals loss of the tight junctions as well as alterations in the morphology of astrocytes. Other experimental evidence has revealed that astrocytes release soluble factors that increase barrier properties and tight junction protein content.
The blood–brain barrier restricts passage of certain ions and substances from the bloodstream to tissues of the CNS.
The presence of only a few small vesicles indicates that pinocytosis across the brain endothelial cells is severely restricted. Substances with a molecular weight greater than 500 daltons generally cannot cross the blood–brain barrier. Many molecules that are required for neuronal integrity leave and enter the blood capillaries through the endothelial cells. Thus, O2 and CO2 as well as certain lipid-soluble molecules (e.g., ethanol and steroid hormones) easily penetrate the endothelial cells and pass freely between the blood and extracellular fluid of the CNS. Due to the high K permeability of the neuronal membrane, neurons are particularly sensitive to changes in the concentration of extracellular K. As previously discussed, astrocytes are foot processes of astrocytes
FIGURE 12.32 • Schematic drawing of blood–brain barrier.
This drawing shows the blood–brain barrier, which consists of endothelial cells joined together by elaborate, complex tight junctions, endothelial basal lamina, and the end foot processes of astrocytes.
responsible for buffering the concentration of K in the brain extracellular fluid (page 369). They are assisted by endothelial cells of the blood–brain barrier that effectively limit movement of K into the extracellular fluid of the CNS.
Substances that do cross the capillary wall are actively transported by specific receptor-mediated endocytosis. For instance, glucose (which the neuron depends on almost exclusively for energy), amino acids, nucleosides, and vitamins are actively transported by specific transmembrane carrier proteins. The permeability of the blood–brain barrier to these macromolecules is attributable to the level of expression of specific carrier proteins on the endothelial cell surface.
Several other proteins that reside within the plasma membrane of endothelial cells protect the brain by metabolizing certain molecules, such as drugs and foreign proteins, thus preventing them from crossing the barrier. For example, L-dopa (levodopa), the precursor of the neuromediators dopamine and noradrenaline, easily crosses the blood–brain barrier. However, the dopamine formed from the decarboxylation of L-dopa in endothelial cells cannot cross the barrier and is restricted from the CNS. In this case, the blood–brain barrier regulates the concentration of L-dopa in the brain. Clinically, this restriction explains why L-dopa is administered for the treatment of dopamine deficiency (e.g., Parkinson’s disease) rather than dopamine.