Key to the Blood Brain Barrier

A signal that controls the integrity of the blood brain barrier - the system that protects and chemically cocoons the brain from the rest of the body - has been discovered...

Early during embryonic development, the cells that line the blood vessels supplying the brain and spinal cord become tightly linked together, establishing a barrier that encloses the central nervous system and permits only certain things to pass through. Others, including immune cells, antibodies, chemicals and many pathogens are screened out.

But what controls the formation and operation of the blood brain barrier wasn't known. Now a team of scientists from Canada have cracked the problem and discovered the molecular key that locks and unlocks the barrier.

It all hinges, Alexandre Prat and his colleagues have shown, on a signal called sonic hedgehog. This is produced by brain cells called astrocytes, which are in contact with the endothelial cells in the blood vessels.

Writing in Science, the team show that, in the presence of sonic hedgehog, endothelial cells bind tightly together, immune cells and proteins are unable to escape from the cerebral circulation and the linings of the blood vessels express fewer cell adhesion molecules making it harder for inflammatory cells to cling on.

Applying a drug called cyclopamine, however, which blocks the action of sonic hedgehog, reversed all these effects. The drug also drammatically worsened the conditions of experimental animals with a multiple sclerosis (MS)-like disease caused by entry into the nervous system of white blood cells that attack the myelin sheath that surrounds nerve fibres. Reducing the integrity of the blood brain barrier appeared to enable more inflammatory cells to flock into the nervous system, amplifying the damage.

In line with this observation, brain samples tested from humans cases of MS show increased levels of sonic hedgehog production in areas where the disease was most active, suggesting that the brain upregulates the signal in an attempt to dampen inflammation.

Together, say the researchers, these data "provide compelling evidence suggesting a dual protective role for the hedgehog pathway at the level of the blood brain barrier and by acting as an endogenous anti-inflammatory system."

Moreover, these findings open up new therapeutic avenues that could be exploited to control entry of immune cells into the central nervous system and therefore reduce the rates of recurrence of MS attacks.