(USMLE topics) Structure, functions of the BBB. Physical, transport and metabolic barriers. Nonbarrier areas. Strategies to overcome the barrier, to deliver therapeutic drugs into the brain.

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The bloodbrain barrier refers to the highly selective permeability of blood vessels within the central nervous system. The barrier controls substances that can enter or leave the nervous tissue. It helps maintain the stable state, or homeostasis, of brain tissue, amid the fluctuations of circulating substances in the blood, many of which can act as neurotransmitters and could create chaos in neuronal activities if allowed to diffuse freely into the brain. The barrier also protects the brain from bloodborne pathogens and toxins.
The bloodbrain barrier is composed of several cell types, including:
Endothelial cells that form the wall of blood vessels;
Mural cells, namely pericytes, partially covering the outside of endothelial cells;
And glial cells astrocytes, whose extended processes, called endfeet, wrap around the vessels.
The endothelial cells alone can fulfill the functions of the bloodbrain barrier, but their interactions with the adjacent cells seem to be required for its formation, maintenance and regulation.
The brain endothelial cells, unlike their counterparts in other tissues, possess unique properties that allow them to tightly control the passage of substances between the blood and brain. These properties can be classified into physical, transport, and metabolic categories:
The brain endothelial cells are held together by tight junctions, which serve as physical barriers, preventing movements of substances through the space between cells.
They have very low rates of vesiclemediated transcellular transport.
They control the movement of ions and substances with specific transporters, of which there are two major types: efflux transporters and nutrient transporters:
+ Efflux transporters use cellular energy to move substances against their concentration gradient. These transporters are usually located on the blood side of endothelial cells. They transport lipophilic molecules, which have passively diffused through the cell membrane, back to the blood.
+ Nutrient transporters, on the other hand, facilitate the movement of nutrients, such as glucose and essential amino acids, into the brain, down their concentration gradient.
The brain endothelial cells also contains a number of enzymes that metabolize, and thus inactivate, certain neurotransmitters, drugs and toxins, preventing them from entering the brain.
An intact bloodbrain barrier is critical for normal brain functions. Neurological diseases such as encephalitis, multiple sclerosis, brain traumas, Alzheimer's disease, epilepsy, strokes and tumors, can breach the barrier, and this, in turn, contributes to disease pathology and further progression.
But not all areas of the brain have the bloodbrain barrier. Some brain structures are involved in hormonal control and require better access to systemic blood, so they can detect changes in circulating signals and respond accordingly. These nonbarrier areas are located around the midline of the ventricular system, and are known as circumventricular organs. Some of their bordering regions have a leaky barrier.
The bloodbrain barrier also has its downside. While it protects the brain from unwanted drugs and toxins, it also prevents therapeutic drugs from entering the central nervous system to treat diseases. Several strategies are developed to overcome this obstacle.