The great German scientist and physician Paul Ehrlich (1854-1915) injected dye into the bloodstream of mice in the late 1800s and found that it penetrated everywhere in the body except the brain (and the rest of the central nervous system).
There is a barrier between the blood and the brain across which a great variety of biochemicals cannot pass. We now know that this blood-brain-barrier is not simply a passive barrier but an active regulator of the internal environment of the central nervous system and learning how to open and close it may lead to cures for many diseases. Understanding of the barrier is summarised by Jeneen Interlandi in Scientific American (June 2013).
The brain is copiously supplied with blood vessels and capillaries – about 600km of tubes. The walls of blood capillaries are lined with endothelial cells. In capillaries outside the central nervous system these cells pack together such that small spaces remain between them, thereby allowing many substances to move readily from the blood inside the capillery to the tissue outside and vice versa. However, the endothelial cells lining the capillaries in the brain pack together so tightly that no intervening spaces are left, thereby preventing the passage of many chemicals across this barrier. This tight packing is the heart of the barrier.
Other cells, called astrocytes and pericytes, envelop the vascular system and contribute to the integrity of the barrier. And other types of cells again called microglial cells help to repair occasional damage that would otherwise breach the containment afforded by the endothelial cells.
Some chemicals, such as water, oxygen and carbon dioxide, can pass across the barrier without any difficulty. Many other essential biochemicals such as glucose and amino acids must be pumped across the barrier through “special channels”. Generally, in order to pass easily a molecule must either be very small (less than 500 times the mass of hydrogen atom) such as most anti-psychotics, anti-depressants and sleep aids, be able to pass through one of the special channels, or be easily soluble in lipid (the heart of the cell membrane barriers of the barrier are lipid in nature) such as alcohol, caffeine, cocaine and heroin. However, about 98 per cent of medicines do not meet any of these criteria, which means they do not cross the barrier or else do so in concentrations so low they are medically ineffective.
Much research is now focusing on how to get medical drugs across the barrier into the brain. One approach is to temporarily prise apart the tight junctions between the endothelial cells lining the blood vessels just long enough to allow drugs to pass through. One way to do this is by applying a concentrated solution of mannitol (a sugar-alcohol) to the endothelial cell layer. This sucks water from the endothelial cells, shrinking them and temporarily pulling them apart. The procedure involves threading a thin catheter through the carotid artery into the brain, infusing a mannitol solution to open the barrier and then infusing the drug which can pass from the capillary blood into the brain. Interlandi describes how brain tumours have been successfully treated by chemotherapy using this technique. This mannitol/catheter technique is also used to administer anti-clotting agents following a stroke.
Research indicates that the barrier plays a vital role in several diseases including multiple sclerosis (MS), epilepsy and alzheimer’s disease. Nerve cells (neutrons) carry electrical signals and are sheathed in an insulating material called myelin. In MS the myelin is attacked and broken down. It now seems that MS episodes (muscle pain, numbness and vision problems) are precipitated by breaches in the integrity of the barrier, allowing too many white blood cells to cross into the brain where they attack the myelin. Epileptic seizures also seem to be triggered by disruptions in the barrier. Devising ways to prevent/repair these could lead to cures for MS and epilepsy.
Finally, research shows that the barrier is established early in embryonic development and is probably crucial to providing the special environment in the brain necessary for neurons to grow and connect. It is suspected that as we grow older subtle changes in the barrier (eg, slow leaks) allow the development of age-related neuro-degeneration. The effects of aging on the barrier will become a new major research focus. I hope it produces results in time to help me!
William Reville is an Emeritus Professor of Biochemistry and Public Awareness of Science Officer at UCC.
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