The Guardian of the Brain: Understanding the Blood–Brain Barrier and its Role in CNS Drug Discovery

Multiple barriers protect the central nervous system (CNS) from external environments, including the blood–brain barrier (BBB), the blood–CSF barrier, and the arachnoid barrier. These barriers regulate the molecular exchange between the blood and neural tissues or fluids. In terms of controlling the surrounding microenvironment of the brain, the BBB exerts the greatest influence. This highly specialized barrier prevents hazardous substances from entering the brain. In addition, a healthy BBB is important for maintaining normal neuronal function. However, due to its unique structure, this barrier not only protects against toxic substances, but also prevents potentially curative compounds from entering the CNS. The BBB is formed by five major components: brain capillary endothelial cells (BCECs), pericytes, astrocyte end feet, the basal membrane in which the endothelial cells and pericytes are embedded, and the neurons surrounding the barrier, which interact closely with the other components. As the BBB has extremely limited permeability, a great number of CNS drug candidates fail in early trials as they cannot pass the barrier. To ensure that CNS drug development is not limited to the 2% of small molecules which are able to pass the barrier via lipid-mediated free diffusion, several drug delivery technologies have been developed in recent decades. BBB drug delivery mechanisms can be broadly classified as invasive, disruptive, and transcellular. Additional factors that impact the permeability, and therefore transferability of the BBB, are individual components such as age, certain diseases, and, especially, disease stages. Understanding these factors and their implications for the CNS drug discovery process is an important step toward more individualized treatment strategies.