blood–brain barrier

blood–brain barrier The main function of the blood–brain barrier (BBB) is to protect the brain from changes in the levels in the blood of ions, amino acids, peptides, and other substances. The barrier is located at the brain blood capillaries, which are unusual in two ways. Firstly, the cells which make up the walls of these vessels (the endothelium) are sealed together at their edges by tight junctions that form a key component of the barrier. These junctions prevent water-soluble substances in the blood from passing between the cells and therefore from freely entering the fluid environment of the brain cells. Secondly, these capillaries are enclosed by the flattened ‘end-feet’ of astrocytic cells (one type of glia), which also act as a partial, active, barrier. Thus the only way for water-soluble substances to cross the BBB is by passing directly through the walls of the cerebral capillaries, and because their cell membranes are made up of a lipid/protein bilayer, they also act as a major part of the BBB.

In contrast, fat-soluble molecules, including those of oxygen and carbon dioxide, anaesthetics, and alcohol can pass straight through the lipids in the capillary walls and so gain access to all parts of the brain.

Apart from these passive elements of the BBB there are also enzymes on the lining of the cerebral capillaries that destroy unwanted peptides and other small molecules in the blood as it flows through the brain.

Finally, there is another barrier process that acts against lipid-soluble molecules, which may be toxic and can diffuse straight through capillary walls into the brain. In the capillary wall there are three classes of specialized ‘efflux pumps’ which bind to three broad classes of molecules and transport them back into the blood out of the brain.

However, in order for nourishment to reach the brain, water-soluble compounds must cross the BBB, including the vital glucose for energy production and amino acids for protein synthesis. To achieve this transfer, brain vessels have evolved special carriers on both sides of the cells forming the capillary walls, which transport these substances from blood to brain, and also move waste products and other unwanted molecules in the opposite direction.

The successful evolution of a complex brain depends on the development of the BBB. It exists in all vertebrates, and also in insects and the highly intelligent squid and octopus. In man the BBB is fully formed by the third month of gestation, and errors in this process can lead to defects such as spina bifida.

Although the BBB is an obvious advantage in protecting the brain, it also restricts the entry from the blood of water-soluble drugs which are used to treat brain tumours or infections, such as the AIDS virus, which uses the brain as a sanctuary and ‘hides’ behind the BBB from body defence mechanisms. To overcome these problems drugs are designed to cross the BBB, by making them more fat soluble. But this also means that they might enter most cells in the body and be too toxic. Alternative approaches are to make drug molecules that can ‘ride on’ the natural transporter proteins in the cerebral capillaries, and so be more focused on the brain, or to use drugs that open the BBB.

Since the brain is contained in a rigid, bony skull, its volume has to be kept constant. The BBB plays a key role in this process, by limiting the freedom of movement of water and salts from the blood into the extracellular fluid of the brain. Whereas in other body tissues extracellular fluid is formed by leakage from capillaries, the BBB in fact secretes brain extracellular fluid at a controlled rate and is thus critical in the maintenance of normal brain volume. If the barrier is made leaky by trauma or infection, water and salts cross into the brain, causing it to swell (cerebral oedema), which leads to raised intracranial pressure; this can be fatal.

The blood–brain barrier is thus a key element in the normal functioning of the brain, and isolates it from disturbances in the composition of the fluids in the rest of the body.

Malcolm Segal

See also acid–base homeostasis; body fluids; cell membrane; cerebrospinal fluid; meninges.