The structure of BBB and different transport pathways for substances across the BBB. (A) The BBB consists of endothelial cells (ECs) surrounded by pericyte and astrocyte endfeet. (B) The tight junction is composed of complex and diverse proteins including transmembrane proteins (claudins and occludins), zonula occludens proteins (ZO-I, ZO-II, and ZO-III), and junction-associated molecules (JAMs). (C) Demonstration of BBB hindering trypan blue entering the CNS in guinea pig embryo. The dye infected almost all of the tissue in the body except most of the brain, which indicates that the CNS is a closed compartment separated from the rest of the embryo [41]. (D) Schematic overview of specific transport pathways through the BBB; larger solutes can pass the BBB by receptor-mediated transcytosis and adsorptive transcytosis. Transport protein could cross the BBB through an active transport mechanism. The transcellular lipophilic pathway allows for lipid-soluble agents to pass the BBB. The paracellular pathway enhances the diffusion of water-soluble agents through tight junctions.