Blood–brain barrier

The blood–brain barrier (BBB) is a highly selective semipermeable border that separates the circulating blood from the brain and extracellular fluid in the central nervous system (CNS). The blood–brain barrier is formed by endothelial cells of the capillary wall, astrocyte end-feet ensheathing the capillary, and pericytes embedded in the capillary basement membrane. This system allows the passage of some molecules by passive diffusion, as well as the selective transport of molecules such as glucose, water and amino acids that are crucial to neural function. The blood–brain barrier (BBB) is a highly selective semipermeable border that separates the circulating blood from the brain and extracellular fluid in the central nervous system (CNS). The blood–brain barrier is formed by endothelial cells of the capillary wall, astrocyte end-feet ensheathing the capillary, and pericytes embedded in the capillary basement membrane. This system allows the passage of some molecules by passive diffusion, as well as the selective transport of molecules such as glucose, water and amino acids that are crucial to neural function. Specialized structures participating in sensory and secretory integration within neural circuits – the circumventricular organs and choroid plexus – do not have a blood–brain barrier. The blood–brain barrier restricts the passage of pathogens, the diffusion of solutes in the blood, and large or hydrophilic molecules into the cerebrospinal fluid (CSF), while allowing the diffusion of hydrophobic molecules (O2, CO2, hormones) and small polar molecules. Cells of the barrier actively transport metabolic products such as glucose across the barrier using specific transport proteins. Technically, the BBB is a shorthand for the Blood-CNS barrier, which has two parts: the Blood-Brain portion and the Blood-Spinal Cord Barrier portion. The two parts are often breached simultaneously, but may be independently breached. The blood–brain barrier results from the selectivity of the tight junctions between endothelial cells in CNS vessels, which restricts the passage of solutes. At the interface between blood and the brain, endothelial cells are stitched together by these tight junctions, which are composed of smaller subunits, frequently biochemical dimers, that are transmembrane proteins such as occludin, claudins, junctional adhesion molecule (JAM), or ESAM, for example. Each of these transmembrane proteins is anchored into the endothelial cells by another protein complex that includes ZO-1 and associated proteins. The blood–brain barrier is composed of high-density cells restricting passage of substances from the bloodstream much more than do the endothelial cells in capillaries elsewhere in the body. Astrocyte cell projections called astrocytic feet (also known as 'glia limitans') surround the endothelial cells of the BBB, providing biochemical support to those cells. The BBB is distinct from the quite similar blood–cerebrospinal fluid barrier, which is a function of the choroidal cells of the choroid plexus, and from the blood–retinal barrier, which can be considered a part of the whole realm of such barriers. Several areas of the human brain are not on the brain side of the BBB. Some examples of this include the circumventricular organs, the roof of the third and fourth ventricles, capillaries in the pineal gland on the roof of the diencephalon and the pineal gland. The pineal gland secretes the hormone melatonin 'directly into the systemic circulation', thus melatonin is not affected by the blood–brain barrier. Originally, experiments in the 1920s seemed to (wrongly) show that the blood–brain barrier (BBB) was still immature in newborns. This was due to an error in methodology (the osmotic pressure was too high and the delicate embryonal capillary vessels were partially damaged). It was later shown in experiments with a reduced volume of the injected liquids that the markers under investigation could not pass the BBB. It was reported that those natural substances such as albumin, α-1-fetoprotein or transferrin with elevated plasma concentration in the newborn could not be detected outside of cells in the brain. The transporter P-glycoprotein exists already in the embryonal endothelium. The measurement of brain uptake of acetamide, antipyrine, benzyl alcohol, butanol, caffeine, cytosine, phenytoin, ethanol, ethylene glycol, heroin, mannitol, methanol, phenobarbital, propylene glycol, thiourea, and urea in ether-anesthetized newborn vs. adult rabbits shows that newborn rabbit and adult rabbit brain endothelia are functionally similar with respect to lipid-mediated permeability. These data confirmed that no differences in permeability could be detected between newborn and adult BBB capillaries. No difference in brain uptake of glucose, amino acids, organic acids, purines, nucleosides, or choline was observed between adult and newborn rabbits. These experiments indicate that the newborn BBB has restrictive properties similar to that of the adult. In contrast to suggestions of an immature barrier in young animals, these studies indicate that a sophisticated, selective BBB is operative at birth.