The Blood–Brain Barrier and CNS Drug Delivery

The blood–brain barriers (BBBs) act as the guardians and as the slaves to the rest of the central nervous system (CNS). By preventing the unrestricted leakage typical of most capillary beds, the vascular BBB then engages in CNS-blood exchanges that are largely regulated in ways not typical in other tissue beds. Thus, the BBBs are not simply barriers, but interfaces that are also endowed with roles that include nutrition, homeostasis, and communication [1]. The barriers adapt to the needs of the CNS, changing with maturation, aging, and in response to environmental challenges. The barriers also adapt or attempt to do so in the face of pathological states and can themselves be the target or the cause of diseases, both peripheral and central. This varied and complex interface provides the basis for a nuanced approach to drug delivery to the CNS. An understanding of the underlying ways in which the BBBs make their livings and serve the CNS provide many different rational approaches to the development of therapeutics that can influence the CNS. As this article will illustrate, these strategies typically involve the delivery of substances from the blood to the brain. But this article will also consider other viable approaches which in some cases do not require the xenobiotic to cross the BBB, such as the blockade of substances that would otherwise cross the BBB (resulting in an antagonist effect), the induction of the release of secondary agents from the abluminal side of barrier tissues, and the modulation of transporter functions. The vascular BBB, in general, and its use in CNS drug delivery in particular is a poorly studied area. Yet, it is much better understood than the other barrier systems, such as the blood-cerebrospinal fluid barrier (BCSFB), the tanycytic barrier, or the blood–retinal barrier. As such, most of this article will emphasize the vascular barrier. However, these other barriers likely follow similar concepts and, with further study, will yield treasure troves of mechanisms and pathways unique to them and useful for the development of therapeutic agents that impact the CNS.