The blood-brain barrier as a target for pharmacological modulation.
The blood-brain barrier (BBB) serves as an exquisitely controlled, functional gate to the central nervous system (CNS). It not only protects the brain from agents in the blood that could impair neurological function, but also controls the influx and efflux of numerous substances to maintain proper homeostasis and provide the brain with necessary nutrients that cannot be produced, de novo. Because the BBB also restricts the entry of many potentially therapeutically useful drugs, researchers have attempted to exploit systems that modulate the BBB in order to increase delivery of therapeutic agents into the brain. Two of the more prominent contemporary approaches are reviewed here. The first involves modulating the permeability of the BBB, focusing on stimulation of endogenous bradykinin receptors constituitively expressed on the endothelial cells of the BBB. The second approach is based on transport across the BBB, utilizing receptor-mediated systems that exist naturally to carry molecules into the brain. The endogenous iron/transferrin transport system has been used extensively preclinically to deliver intravenously administered nerve growth factor (NGF) to the brain and serves as the major focus for this discussion. The underlying principles, recent progress and issues associated with these alternative approaches to delivering therapeutic agents across the BBB are discussed.
Bartus
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Alkermes Inc, Cambridge, MA 02139, USA. rtbartus@alkermes.com