From the liver to the brain across the blood–brain barrier

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Abstract
The burden of brain diseases as established by a recent report of the World Health Organization represents 30% of the total burden of all diseases. This surprisingly high number is clearly related to the fact that the presently available CNS drugs treat only an extremely small percentage of brain diseases, leaving untreated major disorders, such as Alzheimer's disease, brain cancer, and stroke, or minor ones, such as autism, inherited mental retardation, and ataxia. There are also relatively few CNS drugs, although not for a lack of trying. In fact, ceaseless efforts have been made by the pharmaceutical industry to develop CNS drugs, but the number of failures has unfortunately paralleled the thousands of drugs that have been designed and tested. A major stumbling block has remained the fact that very few drugs have the ability to cross the blood–brain barrier (BBB) and reach their targets within the brain parenchyma (1). The BBB is created by the endothelial cells that provide the walls of the blood vessels perfusing the brain. However, in contrast to the peripheral endothelium, the brain endothelial cells lack capillary fenestrations, display low pinocytic activity, and form very tight junctions that are highly resistant to transendothelial ionic fluxes and strictly limit the entrance of endogenous and exogenous compounds into the CNS. How to successfully negotiate the barrier has required a deep understanding of its intimate properties and a great deal of ingenuity. The paper by Spencer and Verma (2) in this issue of PNAS is a good example of the latter with some extra creativity. To fully appreciate …