Peptides and the blood-brain barrier: the status of our understanding

In this limited review, it has only been possible to highlight some of the more significant interactions of peptides with the blood-brain barrier. The literature has been reviewed extensively in recent years, and the major reviews are included in the references. Certainly one of the major outstanding problems is an elucidation of the precise mechanism(s) by which centrally active peptides produce their effects. Without question peripherally administered peptides are able to modify central nervous activity; and for a rapidly growing number of peptides, an extraction by the cerebral endothelial cells can be demonstrated. For some of these peptides, the extraction involves highly specific transporters. What is far less clear is whether this internalization of peptide into the endothelial cells is the first step in a process of transcytosis, with an eventual abluminal exocytosis into brain extracellular fluid of the intact peptide, or an active fragment or whether their entry into brain extracellular fluid is via a different route. If, on the other hand, the mechanism of central action is via the circumventricular organs, a general entry into brain extracellular fluid may not be required. Clearly for different peptides the route and mechanism of action will differ and future attention should be focused on the precise mechanisms producing the central effects of defined peptides.