Entry of EGF into brain is rapid and saturable

Epidermal growth factor (EGF) is a neurotrophic peptide produced both in th e central nervous system and the periphery. Peripheral administration of EG F causes central nervous system-mediated changes. The central nervous syste m effects could be explained by the permeation of EGF across the blood-brai n barrier (BBB). In this report, we show that I-125-EGF crosses the BBB rap idly, with an influx rate of about 2 mu l/g . min, much faster than that fo r neurotrophins, cytokines, and most other bioactive peptides tested. The I -125-EGF was recovered intact in the brain 10 min after i.v. injection, and the majority of the peptide reaching the brain was present in the parenchy ma. The fast rate of influx was significantly decreased by co-administratio n of nonradiolabeled EGF and transforming growth factor cu, peptides that s hare the EGF receptor. By contrast, a monoclonal antibody against the EGF r eceptor failed to inhibit the entry of EGF. Furthermore, mice with a mutati on in the EGF receptor had no significant decrease in the rapid rate of ent ry of I-125-EGF. By contrast to the fast rate of entry, I-125-EGF injected intracerebroventricularly (i.c.v,) only exited the brain with the bulk flow of cerebrospinal fluid. Thus, EGF has a saturable transport system at the BBB for rapid, unidirectional influx. The transport system does not require the entire EGF receptor and is susceptible to possible therapeutic manipul ation. (C) 1999 Elsevier Science inc. All rights reserved.