From time to time, a physician will find a drug that he/she would like to administer to a patient. The problem is that the drug cannot enter the brain. One example is Dopamine.
This could help individuals diagnosed with Parkinson’s Disease but dopamine is unable to cross the blood-brain barrier (or BBB). A cellular and metabolic barrier, the BBB acts as a regulating interface between the brain and the rest of the body.
In all mammals, the blood-brain barrier separates circulating blood and cerebrospinal fluid (CSF) in the central nervous system (CNS). Located at the level of the brain blood capillaries, it is composed of a specialized system of capillary endothelial cells
Narrow capillaries (i.e., blood vessels) are located throughout the brain and body. Highly dense layers of endothelial cells make up the endothelium (i.e., the walls) of these vessels. In most areas of the body, these cells are arranged so that they are separated by spaces: These spaces are large enough to allow the passage of large molecules.
However, in the brain, at the interface between blood and brain, structures called tight junctions seal these cells together at their edges. These tight junctions are also anchored into the endothelial cells. To provide biochemical support, densely packed astrocyte foot processes (called astrocytic feet) enclose the capillaries.
These interendothelial junctions do not allow a free exchange of substances. Instead, they alter the permeability of brain capillaries, selectively filtering substances going from the bloodstream into the CSF and neural tissue. This prevents some solutes, microscopic objects, and large molecules from freely passing between the cells. For example, it thwarts the entry of hydrophilic (i.e., water-soluble) molecules.
Tightly sealed junctions that physically limit transport of solutes form a key component of this barrier. Acting in conjunction as a partial, active, barrier are the astrocyte foot processes. Consequently, the only way hydrophilic substances can cross into the fluid environment of the brain is directly through the walls of the cerebral capillaries.
In these walls, the cell membranes are a lipid/protein bi-layer. This bi-layer (also a major part of the BBB) acts as a passive barrier against the hydrophilic molecules. In contrast, fat-soluble molecules (e.g., oxygen, hormones, carbon dioxide, anesthetics, alcohol) pass directly through.
There is also an active enzymatic barrier. Enzymes (on the lining of the cerebral capillaries) destroy harmful peptides and other small molecules in the blood as it flows through the brain.
Moreover, three classes of specialized efflux pumps (in capillary walls) bind to potentially toxic lipid-soluble molecules that diffuse through capillary walls. According to the literature, these bind to three broad classes of molecules, transporting them out of the brain.
Each of these aforementioned mechanisms is a component of the barrier between the blood and the brain. However, there is also a binding and transport system whereby water-soluble compounds can cross the BBB. This enables substances essential for metabolic activities (e.g., oxygen for respiration, amino acids (AA) for protein synthesis, and so on) to reach the brain.
To achieve this, brain vessels have evolved special carriers on both sides of the cells forming the capillary walls. These actively transport metabolic products (e.g., glucose for energy) across the blood-brain barrier with specific proteins and peptides. Another function is to move waste products and other unwanted molecules in the opposite direction.
Functions
A major function of the BBB is regulating ion flux and supplying nutrients to the brain. In the former, it protects the brain from fluctuations in metabolite concentrations in the rest of the body. By isolating the brain from these changes, it keeps the cerebral levels of ions, amino acids, and peptides constant.
In short, this barrier is crucial to maintain an optimal environment for normal CNS function. Furthermore, when its function is lost, susceptibility to brain diseases may increase.
Because the brain is located in a bony, rigid skull, its volume of fluid has to be maintained in a steady state. The blood-brain barrier plays a critical role in safeguarding this volume: It limits the movement of salts and water from the blood into the extracellular fluid of the brain.
In other body tissues, extracellular fluid is formed by leakage from capillaries. The BBB secretes extracellular fluid at a controlled rate to sustain brain volume. When the integrity of this barrier is compromised (e.g., through trauma, tumors, focal inflammation, infection), water and salts cross into the brain, causing it to swell.
Called cerebral edema, this is an excess accumulation of water in the intra- and/or extracellular spaces of the brain. There is a cascade of events involving loss of the BBB’s integrity, increased tissue pressure, decreased cerebral blood flow, and tissue acidosis. If not treated, this condition can be fatal, or cause severe brain damage.
Another function of the blood-brain barrier is to protect neural tissue from invasion by circulating toxins, bacterial infections, and other harmful molecules. In fact, the barrier is so effective in protecting the brain from bacterial infections, that such infections are rare. Nonetheless, because antibodies and antibiotics cannot cross, infections that do occur are difficult to treat.
The BBB is an effective physiological checkpoint, selectively allowing only certain molecules to move from blood circulation into neural tissue. However, it does allow other substances to enter freely.
Generally, these are low molecular weight, nonionic, and/or fat-soluble molecules. Included are alcohol, caffeine, antidepressants, nicotine, WBCs, and so forth.
Water-soluble and/or large molecules (e.g., those needed to deliver drugs) are not. This is a problem with the blood-brain barrier; it does not differentiate what it keeps out.
Some therapeutic agents that have the potential to be effective may not cross this barrier. In fact, one challenge in treating many disorders is overcoming the difficulty of drugs entering the internal environment of the brain.
In its protective role the BBB can hinder the delivery of many medications necessary to combat various disorders and/or diseases. For example, it restricts the entry of water-soluble drugs used to treat brain tumors and/or infections (e.g., HIV/AIDS virus).
Researchers are endeavoring to develop a greater understanding of how to exploit the components, functions, and changes in the blood-brain barrier with the anticipation this will lead to effective therapeutic regimens. For example, drug uptake across this barrier is altered during inflammation and pathological states involving pain.
The BBB does become more permeable during inflammation and pathological states involving pain. Furthermore, the physiological effects of some disease states affect the ability of a substance to cross. For example, hypertension, edema, and ischemia also cause enhanced permeability. These alterations in permeability may have implications in terms of drug delivery to the CNS.
(References available upon request.)
