Brain targeting of neuroactive drugs: studies of their transport mechanisms as conjugated with vitamin C or glucose.

The employment of prodrugs able to interact with specific transporters of native compound can be an interesting strategy to overcome the problems about the poor absorption of drugs into the central nervous system (CNS) from the bloodstream. We have adopted this strategy taking into account two native compounds widely absorbded into the brain: vitamin C and glucose. Their absorption into CNS from the bloodstream have been identified, respectively, as a Na+ dependent transport involving the transporter SVCT2 localized in the choroid plexus and as a facilitated diffusion phenomenon involving the transporter GLUT1 located in the blood brain barrier. As a consequence, the conjugation of neuroactive drugs with vitamin C or glucose can be a tool to improve their brain delivery by the transporters SVCT2 or GLUT1. We have investigated the aspects related to vitamin C conjugation for potential neuroactive drugs demonstrating that (1) nipecotic acid is transported by SVCT2 only as conjugate; (2) kinurenic acid can interact with SVCT2 as conjugate, even if it can not be transported; (3) diclophenamic acid is a potent inhibitor of the SVCT2 carrier and its conjugate allows us to control the drug release in human blood. We have also demonstrated that dopamine can be transported by GLUT1 carriers only as conjugate with glucose. The transport studies have been performed on human retinal pigment epithelium (HRPE) cells, able to selectively express SVCT2 and GLUT1 transcripts and proteins. A strong correlation can be found between our in vitro results and in vivo neuroactivity of the drugs and their conjugates. The HRPE cells can be therefore propose as an useful model for in vitro studies related to the design of prodrugs of potential neuroactive agents unable to reach the CNS from the bloodstream