The blood-brain barrier keeps over 98 percent of small-molecule drugs out of the brain
Around 1900, Paul Ehrlich injected dyes into animals and found they coloured every organ except the brain. The reason is the blood-brain barrier, a lining of tightly sealed cells in the brain's capillaries that shuts out all large-molecule drugs and more than 98 percent of small ones.
The barrier is built from the endothelial cells lining brain capillaries, stitched together continuously by tight junctions made of proteins such as occludin and claudin-5. Astrocytes wrap the vessels with their end-feet, and pericytes sit within the capillary wall. Oxygen, carbon dioxide, hormones and small fat-soluble molecules under about 400 daltons slip through by diffusion, while glucose and amino acids are carried across by dedicated transport proteins. Pathogens, antibodies and immune cells are kept out, sheltering the brain from immune battles elsewhere in the body.
Its discovery came in stages. An 1898 study noticed that bile salts injected into the blood did not change animals' behaviour. Ehrlich assumed the brain simply took up less dye, but in 1913 his student Edwin Goldmann injected dye straight into the cerebrospinal fluid: the brain stained and the rest of the body did not. The name is often credited to Max Lewandowsky in 1900, though it never appears in his papers, and the Russian scientist Lina Stern, who published in Russian and French, may have coined it.
A few places are deliberately leaky. The circumventricular organs, among them the area postrema, the pineal gland and the lobes of the pituitary, have permeable capillaries so the brain can sample hormones and other signals in the blood and release its own. The barrier is already working at birth.
That protection carries a cost. Blood-borne brain infections are rare but hard to treat, because antibodies are too big to cross and only certain antibiotics can; sometimes drugs have to be delivered directly into the cerebrospinal fluid. Researchers try to open the barrier briefly with osmotic agents, substances like bradykinin or focused ultrasound, to hitch rides on the transporters for glucose, insulin or transferrin, or to send drugs in through the nose along the olfactory and trigeminal nerves. The barrier can also break down in conditions such as Alzheimer's disease, epilepsy, stroke and brain trauma.
Source: Blood–brain barrier
