Which drug causes the most CNS toxicity?
How drugs overcome the barrier
Anatomy of the blood-brain barrier
Six hundred kilometers - roughly the distance between Karlsruhe and Kiel as the crow flies - comprises the system of capillaries that run through the brain. They are extremely important for the safe functioning of the central nervous system, supply the thinking organ with nutrients and at the same time seal it off from foreign substances, including many pharmaceuticals, possibly toxic metabolites and pathogens. At the same time, they protect the cells of the brain from fluctuating concentrations of hormones and neurotransmitters, as well as from changes in the pH of the blood.
Around 100 billion capillaries run through the brain, their average distance is around 40 μm. Different regions of the brain are supplied with different amounts of energy. The density of capillary vessels is highest in the cerebral cortex with 300 to 800 capillary cross-sections per mm2 of tissue. About 610 ml of blood flow through these vessels per minute, the mean flow rate being 1 mm / s.
The vascular endothelial cells of these capillaries are linked by extremely dense closures, the so-called tight junctions or zonulae occludentes, and form the so-called blood-brain barrier, which is a very special challenge for the treatment of CNS diseases. The endothelial cells are supported in their function by the surrounding basement membrane as well as pericytes and astrocytes that sit on the outside of the capillaries.
The basement membrane consists of heparin sulfate proteoglycans, fibronectin, type V collagen, laminin and other extracellular matrix proteins. The exact function of the cells on it has not yet been fully clarified; possibly they release growth factors to the endothelial cells. It is known that astrocytes release a number of messenger substances that can modulate the permeability of the endothelium in the range of seconds to minutes. They also produce a large part of the cholesterol found in the brain. Cholesterol cannot cross the blood-brain barrier and therefore has to be synthesized locally within the brain.
All vertebrates have a blood-brain barrier and almost all of them form an endothelial barrier, in which the tight junctions of the endothelia make a significant contribution to the barrier effect. Only in cartilaginous fish, to which the sharks and rays belong, and in the sturgeon family, the barrier effect of the blood-brain barrier is guaranteed by the perivascular astrocytes.
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